Co-Founder and Chief Executive Officer
Mr. Joffry Maltha is Co-Founder and Chief Executive Officer of CytoSMART Technologies. He brings a track record of commercializing new technologies. Mr. Maltha began his career at Nedap NV. He held several positions as product development manager and as international business development manager. From 2009 – 2015 he was CEO at Vabrema BV (Eindhoven, The Netherlands). Mr. Maltha received a Master of Science degree in Technology Management from the Technical University of Eindhoven where he graduated cum laude.
Cell-Imaging: Bringing a New Technology to Market in Partnership
Cell imaging is a common task for assessing cell health as part of the culture process which uses the tools from major established suppliers. So working with these is essential for success. However working with a larger company as a partner requires a good appreciation of how they work: their processes, priorities be that in production, QA or marketing. CytoSMART has succeeded in building such relationships
Daniel Irimia is a bioengineer, medical doctor by training, and passionate researcher. His work leverages the most advanced microfluidic technologies to study the responses of neutrophils to infections, inflammation, and sepsis and bring forward new capabilities for diagnostic and monitoring in the clinic. He is now an Associate Professor in the Surgery Department at Massachusetts General Hospital and Harvard Medical School.
Inflammation-on-a-Chip – High-Throughput Microscale Arrays for Neutrophil Swarming
Neutrophil swarms protect healthy tissues by sealing off microbes from healthy tissues. Most swarming experiments are performed in animals. However, the throughput of experiments is low and physical access to the molecular signals coordinating neutrophil swarming is limited. Here, we report on the development and validation of large microscale arrays of targets for the study of human neutrophil swarming. We characterized the synchronized growth of thousands of swarms at once, towards live-microbe and microbe-like synthetic particles. We found that neutrophil swarming in patients following major trauma is deficient and these deficiencies resolve over time.
Senior Research Scientist
Scaling-Up Drug Discovery in the Fourth Dimension
Kinetic and mechanistic in-vitro characterisation of compounds yields critical predictive information on their potency in cellular assays, DMPK profile, and in-vivo performance. Thus, the ability to characterise more compounds this way in early SAR profiling holds substantial benefit. Scalable instrumentation and lab automation to this end is available now. However, the complex data analysis easily takes a day per experiment, severely limiting throughput.
This talk outlines recent progress in developing plate based kinetic techniques along with advances in data analysis. A new software solution reduces analysis times ten-fold, while ensuring scalable, consistent, reliable processing of biophysical and mechanistic assays and direct publishing of results on a corporate level for effective ranking of lead series. With this new approach, we aim to dramatically scale up compound characterization embedded in a streamlined and modern pharma research workflow.
References: Swinney, David C. Current Topics in Medicinal Chemistry, 6, 2006, pp. 461-478
Copeland Robert A. Nature Reviews Drug Discovery, 15, 2016, pp.87–95
Schiele Felix et. al, Analytical Biochemistry, 468, 2015, pp 42-49
Associate Principal Scientist
Erik Müllers works within the Cardiovascular, Renal and Metabolic diseases IMED as well as the global Discovery Sciences organization at AstraZeneca in Gothenburg. He focusses on high-content, cell-based microscopy and flow cytometry assays and data analysis strategies to support target identification and drug discovery projects at an early stage of the drug discovery pipeline.
Dr. Müllers earned his Ph.D. at Dresden University and the MPI for Molecular Cell Biology and Genetics, establishing high-content flow-cytometry and live-cell microscopy applications to study retroviral replication. Followed by a Postdoc at Karolinska Institutet in Stockholm, where he developed novel imaging-based cell models to investigate molecular regulation of cancer cell biology and DNA damage response.
The Impact of Cell Models Used in Drug Screening: Lessons Learned from Multiplexed, High-Throughput Flow Cytometry
Erik Müllers, Johan Brengdahl, Mikolaj Slabicki, Mei Ding, Catharina Wising, Thorsten Zenz, and Tyrell Norris
The high failure rates in turning preclinical drug candidates into new medicines have increasingly raised questions about predictiveness and translatability of the cell-based models currently used in drug screening.
Flow cytometry allows multiplexing of assay read-outs at single cell resolution. However, only due to recent technical advances has flow cytometry become applicable for high-throughput drug screening. We have used this advancement to test the importance of the cell model in small molecule drug screening. We developed a screen in 384-well format, using automated liquid handling and high-throughput, high-content flow cytometry on the Intellicyt iQue Screener Plus. The assay was developed as a multiplexed assay to simultaneously screen for small-molecule modulators of CD20 and CD38 cell surface expression as well as cell proliferation in two lymphoblast cell lines. To achieve this, dye-based cell encoding was used to multiplex BJAB and Raji cell lines in the same well. Having established this information-dense assay we screened an in-house library of more than 20,000 target-annotated compounds. We identified close to 600 hits (hit rate 2.9%) comprised of different phenotypes between the two cell lines.
We will present the screen outcome and analysis revealing the degree of overlap and non-overlap between the two cell models, demonstrating the feasibility and increased predictive power of multiplexed, high-content flow cytometry screening. Moreover, our data highlights the importance of the cell model selection for primary drug screening.
Co-Founder and CEO
Stefan Braam is the Co-Founder and CEO of Ncardia. Stefan brings Ncardia over a decade of experience in stem cell technology, product development and general management. Before the appointment as CEO of Ncardia, Stefan was the CEO of Pluriomics. As co-founder and key inventor of Pluriomics/Ncardia technologies, he has been instrumental in the establishment and growth of the company. Earlier in his career, Stefan obtained a MSc and Ph.D. (both cum laude) in stem cell biology under the supervision of Prof. Dr. Mummery and obtained international experience in labs in the UK and Australia. Stefan won the NGI venture challenge (2009), the Niaba biobusiness Masterclass (2010), published in multiple leading scientific journals, is an inventor on multiple patent families, secured multiple grants and commercial research collaborations and was with increasing responsibilities instrumental in Pluriomics/Ncardia pre-seed, seed, Series A and B financing rounds.
iPSC Derived Cardiomyocytes; How Validation in Cardiac Safety Pharmacology Opens the Door for New Applications in Drug Discovery and Development
Cardiotoxicity and lack of efficacy are major reasons for compound attrition in late-stage pre-clinical and clinical development. To avoid such failures in costly clinical phases, physiologically relevant predictive cellular assays should be exploited in early preclinical phases. Traditional in vitro cardiac testing platforms have two main drawbacks. On one hand the physiologically relevant human models such as primary human cardiomyocytes cultures are not readily available for (high throughput) assays and on the other hand, HTS compatible models, such as engineered cell lines, lack the relevant physiological responses required for highly sensitive and predictive compound screening. The availability of hiPSC-derived cardiomyocytes (hiPSC-CMs) has led to the development of several cell-based assays allowing detection of changes in electrophysiology, cardiotoxicity and compound efficacy.
In my presentation, I will give various examples of how iPSC derived cardiomyocytes have been validated and now are routinely used in safety screening by the pharmaceutical industry. I will discuss how validation of these cellular models for safety assessment has impacted safety assessment studies and how the models currently find their way to high throughput drug efficacy screening applications.
Finally, I will also discuss how the iPSC-derived cardiomyocyte assays for the prediction of drug-induced cardiac arrhythmias can serve as an example for other cell-based assays in the cardiac and neuronal field.
Senior Principal Scientist
Hinrich Goehlmann studied Biology at the Technische Hochschule Darmstadt, Germany, receiving his Diplom in 1995. His thesis was based on glycolysis research on the yeast Saccharomyces cerevisiae in the group of Prof. F.K. Zimmermann. In 1995 he joined the group of Prof. R. Herrmann at the Zentrum für Molekulare Biologie of the University of Heidelberg, Germany. He received his doctorate degree for his work on microarray-based whole genome expression analysis of Mycoplasma pneumoniae in 1999. Following this, he joined the department of Functional Genomics at Johnson & Johnson Pharmaceutical Research and Development in Beerse, Belgium as Postdoctoral Fellow. Dr. Goehlmann currently holds a position as Senior Principal Scientist heading a team within Computational Sciences responsible for the analysis of high dimensional biology data sets from Next-Generation Sequencing (NGS), microarrays and High Content Imaging (HCI). In 2005 he was awarded Johnson & Johnson’s Philip B. Hofmann Research Scientist Award for his contribution to the NGS-based elucidation of the mechanism of action of Bedaquiline, a novel antibiotic for the treatment of tuberculosis.
Characterization of the Janssen Screening Library Using Transcription Signatures for Hit Discovery and Expansion
Between 2015 and 2017 we have generated L1000-based gene-expression profiles of 230,000 compounds from the Janssen screening deck. To maximize what we can learn about the compound-induced transcriptional effects, we profiled each compound in two different cell systems. Besides applying the data for hit expansion, we have also built and validated a machine-learning based target-prediction system that utilizes L1000 data but also High Content Imaging data as well as chemical information and primary assay data to prioritize compounds for screening. Our efforts have already resulted in the discovery of compounds of interest in multiple therapeutic areas.
The talk will briefly touch upon our motivation to do this large experiment, describe where we currently are in using such high dimensional biology data and end with our view on how we hope to further increase the impact of the data from these profiling technologies.
Director of Chemical Biology
Iván Cornella-Taracido is the Vice-President of Chemical Biology and Proteomics at Cedilla Therapeutics, a recently created Third Rock Ventures company based in Cambridge, MA, harnessing intrinsic protein stability mechanisms to broaden the reach of small molecule therapeutics.
In his prior career at Novartis, Sanofi, AstraZeneca and Merck & Co. (MSD in Europe), Iván has contributed to create and lead Chemical Biology teams responsible for the implementation of strategies to support target discovery across several disease areas, integrating chemical genetics and chemoproteomics with medicinal and synthetic chemistry, molecular biology, phenotypic screening, cellular pharmacology and informatics.
Prior to moving to pharma, Iván was a US National Cancer Institute Initiative for Chemical Genetics Research Fellow at the Institute of Chemistry and Cell Biology of Harvard Medical School and NIH Postdoctoral Research Fellow at Boston College. He received his Ph.D. from the Universidade da Coruña (UdC), Spain.
Research and Technology Development
After his graduation from Ernst-Abbe-Hochschule Jena, University of Applied Sciences, he worked as a software developer and scientific assistant in the field of operation research. 1998 he switched to OPAL Jena GmbH, the precursor of CyBio AG, now an integrated part of the Analytik Jena AG. Here he worked several years as a software developer, software architect and project manager on software for laboratory automation solutions before he 2006 tokes over the responsibility for the software product management. From 2010 he led the software and electronic development team of the CyBio product line. Since 2017 his main work is the development of product strategies around digitalization and industry 4.0 as part of the research and technology development team.
Reduce Complexity Through Application-Oriented Approaches
Dr. Paul Boutros pursued his undergraduate education at the University of Waterloo in Chemistry, with co-op training ranging from water-purification to petrochemicals. But he found his true calling during a work term at Michigan State University developing computer models of drug response. His undergraduate thesis on modelling DNA damage received first place at the National Undergraduate Chemistry Conference. In 2004, he started a Ph.D. at the Ontario Cancer Institute, where he received the CIHR/Next Generation First Prize and an Invitrogen Canada Young Investigator Silver Award. He received his Ph.D. in 2008 and started his independent research career at the Ontario Institute for Cancer Research, where he remains today. Dr. Boutros co-leads the Canadian Prostate Cancer Genome Network and leads an international consortium optimizing algorithms for genomic data analysis. He is a Terry Fox Research Institute New Investigator and has been named Prostate Cancer Canada Rising Star in Prostate Cancer Research.
Using Computational Techniques to Understand the Origins of Cancer Aggressivity
Human cancers are remarkably variable in their initial presentation. They can arise in almost every organ of the body, at almost any age. Even within a single tumour type, they vary dramatically in morphological characteristics, like their size, location within an organ and cellular structure. These larger changes are reflected in, and presumably are partially driven by, differences in the specific somatic mutational characteristics of tumours. Indeed, while individual tumours can harbour tens to hundreds of thousands of mutations, the median number shared by any pair of cancers is zero. These morphological and molecular heterogeneities are mirrored by a remarkable heterogeneity in clinical outcomes. There thus remains an urgent need to understand which tumours are highly aggressive, and which are not, so that therapies can be tailored to individual patients and both over- and under-treatment prevented.
We systematically evaluated of the origins of differential tumour aggressivity. Initially using prostate cancer as a model tumour type, we quantified the relative contributions of somatic mutational features, epigenomic features, transcriptomic features and proteomic features. Ultimately we discover that aggressivity is a complex function of all these, and is driven not only by those mutations present at diagnosis but also by the evolutionary trajectory upon which the tumour is progressing. Finally, we evaluate why evolutionary trajectories differ within and between a broad range of cancer types, and offer suggestions for the derivation of evolutionarily-aware biomarkers.
Head of the Technology Development Studio
Marc Bickle obtained his Ph.D. at the Biozentrum in Basel, Switzerland, studying the immunosuppressive drug Rapamycin. He then went to the LMB in Cambridge, UK, to study the genetics of behaviour in C. elegans. He then participated in the creation of Aptanomics, a drug discovery Biotech in Lyon, France. He is currently heading the Technology Development Studio at the MPG-MPI in Dresden, Germany, performing functional genomic and chemical screens.
Senior Research Scientist
Graduated in 2000 from the University of Liverpool with a degree in Genetics and joined the High Throughput Screening (HTS) department of AstraZeneca in 2001. Jarrod’s current role is a Senior Research Scientist within the Global High Throughput Screening Centre that forms part of AstraZeneca’s Discovery Sciences function. During his 14 years in company, Jarrod has worked extensively with screening applications, assay development activities and biophysical technologies. Since 2012 Jarrod has focused on devising approaches to identify and eliminate compounds that function via undesirable mechanisms of action to improve the quality of hit to lead compounds. His work interests include the application of biophysical techniques and development of new technologies to improve drug discovery screening and hit identification activities.
Performing a High Throughput Screen to Identify Small Molecule Enhancers of Antisense Oligonucleotide (ASO) Uptake
One key aspect constraining the use of antisense oligonucleotide (ASO) drugs is the poor membrane permeability of the large polar molecules. This limits their access to intracellular targets thus diminishing their therapeutic effect. Recently several examples of small molecule enhancing either oligonucleotide uptake or their intracellular release have been reported presenting a novel opportunity for combination treatments to boost their efficacy. This presentation describes the successful development and prosecution of a world first high throughput screen (HTS) to identify compounds with ASO uptake/intracellular release enhancing properties. We detail the unique challenges of the quantitative, reverse transcriptase PCR assay that was employed highlighting key automation issues that needed to be overcome. Finally, we offer insight into the complexity of analysing the output from such screens with recommendations on how the process could be evolved in the future.
References: Yang, B. et al, Nucleic Acids Res. 2015 Feb 27; 43(4): 1987–1996
Scientist in the Antibody Discovery and Protein Engineering Group
I am a lab-based scientist in the Antibody Discovery and Protein Engineering group at MedImmune based in Cambridge, United Kingdom. I specialise in Assay Technologies and I have over 10 years of industry experience in developing and optimising a wide range of biochemical and cell-based functional assays including HTRF, Mirrorball, flow cytometry, cell signalling and reporter gene assays. I previously studied for a BSc degree in Applied Biology at the University of Bath and a Masters in Physiology at the University of Liverpool.
Strategies for Identifying Biologics with Specific Mechanisms of Action
There are many important properties to consider when isolating and selecting leads in early antibody drug discovery. These include; function, potency, specificity, selectivity, affinity and developability. Assays and screening cascades can be designed at the project outset to triage thousands of antibodies for these desired properties. While screening for function early is paramount, it is also important to understand the mechanism of action through which an antibody-drug mediates its functional effects (e.g. competitive, non-competitive, allosteric), to ensure that maximal target suppression can be achieved in vivo. Using case studies, this presentation will highlight strategies and learnings in identifying antibody biologics with the desired mechanism of action.
Associate Research Fellow
Hit Triage and Validation for Phenotypic Screening: Considerations and Strategies
Phenotypic drug discovery approaches can positively affect the translation of preclinical findings to patients. However, significant differences exist between target-based and phenotypic screening, prompting a need to re-assess our strategies and processes to most effectively prosecute phenotypic projects. Phenotypic screens have dual goals of delivering both efficacious compound series as well as novel molecular targets for diseases of interest whereas only desirable chemical matter is sought for target screens. Hits acting through a number of (largely unknown) mechanisms in a large and often poorly understood biological space need to be triaged to differentiate desirable mechanisms from undesirable ones.
Given these fundamental differences, the hit triage and validation process were critically re-evaluated in light of the unique characteristics of phenotypic screening. Key considerations and specific strategies will be shared and exemplified with in-house and literature case studies.
Dr. Kuan Yan (DOB: 1982-12-30) is the chief informatics officer (CIO) of OcellO Netherlands. In 2013, he received the Ph.D. title from Leiden University (Netherlands) in the field of bio-imaging and image analysis. He has dedicated so far 12 years to the field of image analysis and software design for 3D high-throughput/high-content screen (HTS/HCS) solution. His major contributions to the research community include 20 journal publications. At OcellO, his main focus is leading the development of OcellO OMiner(TM) analysis platform and providing analysis service for commercial HTS/HCS project.
HT Analytics at the Different -omics Levels
Image-Based Quantification of Immunotherapies Effects in 3D Environment
Delivering on the promises of cancer immunotherapy is hampered by a lack of in vitro testing platforms that enable early treatment selection. Compared to conventional 2D culture, 3D cultures can reproduce tissue organization and recapitulate complex cell-cell interactions. However, readouts are typically limited to biochemical measurements of viability or cytokine release and the rich phenotypic information describing critical interactions between immune cells and tumor is squandered. We therefore extended OcellO’s service to enable the 3D analysis of interactions between tumor and immune cells in a 3D co-culture system. Via 3D co-culture and image-based analysis, various immune-tumor interactions such as infiltration or killing can be visualised and quantified. This represents a new, highly powerful tool for cancer immunotherapy drug developers to select the most promising treatments and understand better the spatial cellular context not detected by alternative techniques.
As co-managing director and co-founder of MIMETAS, Paul closed deals with most top-10 pharma companies, secured a series A investment round and enabled mass production & global marketing of OrganoPlates. Prior to founding MIMETAS, Paul worked for the high-tech company Silicon Biosystems in Bologna, the Institute for Microsystems Engineering (IMTEK) at the University of Freiburg and the Leiden Academic Centre for Drug Research, Leiden University. Paul holds a cum laude masters degree in Biomedical Engineering and a cum laude PhD degree in Microsystems Engineering.
The OrganoPlate: Human Organ-n-a-Chip Tissue Models for Predictive Drug Testing in Any Throughput
Organ-on-a-chip has recently emerged as the new paradigm in enhanced, 3D tissue culture. The field builds on almost 26 years of developments in microfluidic and associated microfabrication techniques on the one hand and an urge towards ever more physiologically relevant cell and tissue culture approaches on the other hand. Application of microengineering techniques in cell culture enables structured co-culture, 3D culture, the use of flow and associated shear stress and application of controlled gradients. MIMETAS develops a commercially available platform based on a microtiter plate format that harbors up to 96 chips and enables perfused 3D co-culture in a membrane-free manner. The OrganoPlate® facilitates growth of tubules and blood vessels under continuous flow of medium, it allows engineering of organ complexity without usage of artificial membranes. The OrganoPlate® is fully compatible with liquid handling equipment and high-content readers and is easily adopted by end-users. Current flagship models in OrganoPlates® comprise the human kidney proximal tubule, central nervous system, colon, liver and blood vessels. These models are unsurpassed in terms of physiological relevance and throughput.
Thomas G. Labrecque Professor
Stephen J. Andriole is the Thomas G. Labrecque Professor of Business Technology at Villanova University where he teaches and directs applied research in emerging digital technologies and business technology management. He is formerly a Professor of Information Systems & Electrical & Computer Engineering at Drexel University and the George Mason Institute Professor and Chairman of the Department of Information Systems & Systems Engineering at George Mason University. Dr. Andriole was the Director of the Cybernetics Technology Office of the Defense Advanced Research Projects Agency (DARPA), where he founded the MIT Media Lab, Yale’s artificial intelligence Labs, open source analysis, early warning systems and research supporting the ARPANET (that evolved into the Internet & World Wide Web). He was the Chief Technology Officer and Senior Vice President of Safeguard Scientifics, Inc., and the Chief Technology Officer and Senior Vice President for Technology at CIGNA Corporation. His most recent book is The Innovator’s Imperative: Rapid Technology Adoption for Digital Transformation (CRC Press, 2017). He has published articles in the Sloan Management Review, Software Development, IEEE Software, the Communications of the ACM, the Communications of the AIS, IEEE IT Professional and the Journal of Information Technology Research, among other journals. He did his undergraduate work at LaSalle University and earned his M.A. and Ph.D. at the University of Maryland @ College Park. More information about Dr. Andriole’s career can be found at www.andriole.com.
HT Analytics at the Different -omics Levels
This presentation will explore the intersection of three worlds: augmented analytics, nutrigenomics and pharmacogenomics. The presentation will describe the range of augmented analytics methods, tools and techniques, such as automated data preparation, structuring, discovery and analysis – especially automated predictive analytics. The intelligent search for correlations and prescriptions will drive nutrigenomics and pharmacogenomics – and other applications areas – to new products and services. The current methods, tools and techniques are tried-and-true – but slow. Augmented analytics will not only accelerate the search for correlations across therapeutic areas and genes, but it will also find correlations across applications areas, such as nutrition. The end game – if there ever is one – is wider and deeper personalized life management where genomics is broadly correlated with healthcare, activities and lifestyles.
Patrick R. Gentry is a chemical biologist whose research has focused on the development and characterization of small molecule ligands for G protein-couple receptors (GPCRs). In 2014 he received his Ph.D. from Vanderbilt University in the laboratory of Craig Lindsley. His doctoral research focused on the discovery, synthesis, and characterization of novel, subtype-selective ligands for the M5 muscarinic acetylcholine receptor. Following his Ph.D., Patrick joined the laboratory of Arthur Christopoulos at Monash University. There he continued his work on the M5 receptor, studying both the structure of the receptor as well as the molecular-level interactions of the receptor with allosteric modulators.
In 2017 Patrick joined the Hans Bräuner-Osborne group at Copenhagen University. Currently he is leading a screening campaign to discover novel small molecules for orphan GPCRs. His studies utilize unbiased dynamic mass redistribution assays in concert with hypothesis-based libraries of small molecules specifically tailored to target the orphan GPCRs under study. To date, this effort has revealed multiple compounds with high selectivity for individual orphan GPCRs, representing valuable new probes for the study of these relatively unknown targets.
Development of Novel Probes for Orphan G Protein-Coupled Receptors
G protein-coupled receptors (GPCRs) are vital mediators of cell function and their malfunction is associated with many disease states. Despite this importance, 35% of non-olfactory GPCRs are classified as “orphans”, that is, their endogenous ligand is not known. A key challenge to the study of orphan GPCRs is the lack of selective tool compounds. We have screened computationally designed libraries of putative ligands tailor-made to link orphan receptors to small molecules with a high degree of selectivity, affinity, and potency. The libraries build on cheminformatics mining of over 144,000 GPCR ligands and virtual screening of pharmacophores based on all available GPCR structural data. Libraries were screened in the Corning Epic dynamic mass redistribution assay to measure holistic cellular response. This innovative approach to library design coupled with holistic screening assays has enabled us to discover a collection of novel tool compounds with which to study orphan GPCR biology.
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Gijs is very fond of nature, hence he studied biology and a Ph.D. in experimental immunology. Meeting a beautiful Spanish PI in Amsterdam was a happy coincidence that made him relocate to Spain as a PostDoc. His language skills and Dutch pragmatism kickstarted his career in a multinational environment, first in Big Pharma, then sales and marketing at Baxter followed by Promega, an innovative reagent supplier. Crucial for him has been to stay close to science on this journey, while realizing that the commercial world isn’t as bad as they told him in university, in fact it’s good fun and it has allowed him to broaden his scope and get to know many different parts of the world.
Head of the Innovative Tools&Solution Unit
I obtained my Ph.D. in Molecular and Cellular Biology at Open University of London, UK/Dibit, Milan, ITA in 2004 and I continued my postdoctoral studies in neurobiology with John Rubenstein at University of San Francisco, USA. In 2010 I returned to Italy and I joined the laboratory of Elena Cattaneo at University of Milan working on the neuronal differentiation of hES and iPS cells. In 2016 I took the role of Principal Scientist at Axxam, Milan working on cellular assay development. In 2018 I became Head of the Innovative Tools&Solution Unit at Axxam, leading a three-labs unit, including Molecular Biology, Cell Factory, and iPS cells lab. My current research interest include the automation and miniaturization of processes to bring iPS cells into HTS.
Metabolic Pathologies with High Medical Needs: Research and Development of New Pharmacological Approaches and Innovative Molecular Targets
The identification and development of novel pharmacological agents with new mechanisms of action to treat metabolic diseases, such as Type I diabetes and its most common complication diabetic nephropathy is the goal of the presented project. Our aim is to recover the functionality of the autophagic process, whose impairment has recently been demonstrated to be responsible for the damage of the kidney cells podocytes. One of the most promising druggable targets is the lysosomal Calcium channel Mucolipin-1 (TRPML1) recently described to guarantee an efficient autophagic flux. Different strategies will be followed to develop a panel of different cell-based assays, suitable to be used in High Content (HC) and High Throughput Screening (HTS) platforms to screen and identify small molecules able to stimulate the autophagic processes and to further validate the capability of the newly identified TRPML1 activators on restoring the impaired autophagic and lysosomal storage processes.
Senior Research Scientist
At Promega, James is focused on the development and application of target engagement technologies to investigate drug-target interactions in live cells using NanoBRET. He is broadly interested in applying this technology to enable kinome-wide evaluations of live-cell inhibitor selectivity. Prior to joining the team at Promega, James received his Ph.D. in Biochemistry from the University of Wisconsin Madison, where he focused on developing inhibitors for the collagen prolyl 4-hydroxylases (CP4Hs), a group of enzymes implicated in myriad diseases including fibrosis, scurvy, and cancer. James has contributed to the discovery and patenting of a novel and selective human CP4H inhibitor, which is currently in pre-clinical investigations. Lastly, James received his Bachelor of Science degree in Biochemistry from Lafayette College in Easton, Pennsylvania, where he focused on using analytical methodologies to discover small-molecule biomarkers of parasitic infections.
A Quantitative Target Engagement Approach to Profile Thermodynamic and Kinetic Selectivity in Live
Until recently, no approaches have been described that allow for a quantitative assessment of target occupancy in live cells at thermodynamic equilibrium. Here we report the application of an energy transfer technique (NanoBRET) that enables the first quantitative approach to broadly profile target occupancy, compound affinity, and residence time. Using kinases as a model, we demonstrate that target engagement potencies correlate strongly with results from conventional pathway analyses. Moreover, this technique allows for broad-spectrum profiling of inhibitor selectivity against a diversity set of nearly 200 kinases in a simple work-flow. We performed a systematic comparison of kinase inhibitor selectivity in live cells. Compared to published biochemical datasets, we observed improved intracellular selectivity for certain clinically-relevant multi-kinase inhibitors. Mechanistic analysis suggests that micro-environmental ATP levels contribute significantly to the observed selectivity.
Vice President, Translational Oncology
Henry QX Li, Ph.D. is currently Sr. VP of Crown Bioscience, responsible for the company’s global research and innovation, with focus on the Crown’s oncology efforts. CrownBio is a global platform-technology and service company specialized in preclinical and translational oncology, CVMD and inflammatory diseases. Dr. Li has been directly responsible for the building of the largest PDX platforms (library of >3000 annotated PDXs (HuPrime), various immune-oncology platforms (libraries of homograft mouse tumours (MuPrime) and HuGEMM, etc.), as well as biomarker and diagnostic platforms.
Prior to joining Crown, Dr. Li has 20 years of biopharmaceutical, as well as academic R&D, experiences in cancer and viral infection, including leadership roles as R&D director/senior director roles in several US-based biotech companies. Dr. Li currently also holds visiting Professor position at Peking University-State Key Laboratory. He earned his Ph.D. in Molecular Biology/Biochemistry from University of California (Irvine) and completed his postdoctoral training at UCLA School of Medicine. He has published ~70 manuscripts and edited 3 books in the biopharmaceutical areas.
PDX as a Discovery and Translational Platform for Targeted and I/O Strategies
Cancers are diverse diseases of genetic and immunological abnormalities, rendering any given treatment only effective for a small subset of patients. Discover and develop different therapeutics tailored to certain patient populations are thus essential. First, the genetic heterogeneity is largely determined by tumour cells, including various oncogenic driver mutations which become the foundation of targeted therapy. Second, heterogeneous tumour microenvironment (TME), particularly tumour-infiltrate immunity, plays critical role in cancer pathogenesis, prognosis and response to immuno-oncology (I/O) therapy. Targeting either or both will be the future of cancer therapy.
Patient-derived-xenograft (PDX) mimics patient, particularly genetically (e.g. driver), and is thus particularly useful to validate investigational targeted therapy at preclinical setting (hypothesis testing). For instance, our recently created unique acute myeloid leukemia (AML) PDX with IDH2 mutation have helped our pharmaceutical partner to demonstrate proof of concept of IDH2 targeting for the treatment of IHD2-mutated AML, which subsequently guided clinical testing and ultimately enabled the recent accelerated regulatory approval of first-in-class Enasidenib last year1. In addition, a library of PDXs represent diversity of patients and can support population-based study (mouse clinical trial) that mimic human trial and also enables hypothesis generation and discovery of predictive biomarkers, such as those for cetuximab2, 3.
PDX has yet to be used for immuno-oncology (I/O) research for lack of immunity4. Most preclinical I/O research are usually conducted using surrogate mouse models. Investigating TME-specific components at molecular levels is rather challenging for the difficulty to separate stroma from tumour cells, either physically via microdissection and single-cell isolation or in silico via bioinformatics. However, PDX may be a powerful system to study TME, where human and mouse content can readily be separated in silico. We transcriptome-sequenced ~1600 bulk PDX tumours. By aligning reads to human and mouse genomes, we identified all types of TME components, including adaptive and innate immune cells. The corresponding fractions vary across cancer types and individual models. Using co-regulation analysis, we also identified certain number of inter-species interactions, or tumor-TME interaction, that vary greatly among cancer types. These interactions likely play roles in tumour growth, and thus potentially targetable for novel TME related drug intervention, including novel I/O. Our data clearly support these interactions being critical to tumour growth since the numbers of interaction are reversely correlated to the transplantation take-rate of corresponding type of PDX as anticipated. Our data also clearly suggest the role of KRAS mutation in tumour growth independency on TME, hinting potential challenges in treating these type of cancers. Currently, efforts have been focused on discovering important tumor-TME interactions that can help understand disease mechanisms and potentially be explored to develop new cancer treatment strategy.
1. Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, Chen Y, Nagaraja R, et al. AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations. Cancer discovery 2017;7: 478-93.
2. Zhang L, Yang J, Cai J, Song X, Deng J, Huang X, Chen D, Yang M, Wery JP, Li S, Wu A, Li Z, et al. A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. Sci Rep 2013;3: 2992.
3. Chen D, Huang X, Cai J, Guo S, Qian W, Wery JP, Li QX. A set of defined oncogenic mutation alleles seems to better predict the response to cetuximab in CRC patient-derived xenograft than KRAS 12/13 mutations. Oncotarget 2015;6: 40815-21.
4. Li QX, Feuer G, Ouyang X, An X. Experimental animal modelling for immuno-oncology. Pharmacol Ther 2017;173: 34-46.
co-PI of the Kallioniemi Research Group
Päivi Östling has since 2011 been working on precision medicine in solid tumours first in prostate cancer and now also in renal and bladder cancer. This work has been part of a team science effort linked to the “Grand Challenge” on Individualized Systems Medicine, initially focused on leukaemia but now including also solid tumours. This work was initiated at the Olli Kallioniemi research group, at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland and has now expanded to the Science for Life Laboratory (SciLifeLab), Department of Oncology and Pathology, Karolinska Institutet, Sweden. Päivi currently operates as the co-PI of the Kallioniemi research group at SciLifeLab with specific focus on developing the next generation precision cancer medicine.
Precision Systems Medicine from Leukaemia to Solid Tumours
Most precision cancer medicine efforts are based on the identification of oncogenic driver mutations by genome sequencing. We believe that this will miss therapeutic opportunities and additional profiling technologies as well as cell-based functional testing should be included. This systems approach requires disease-relevant ex vivo cell models, multi-parametric assays, quality metrics, automated analytics pipelines and integration with –omics profiling to enable actionable information to the clinic.
Our studies in leukaemia indicate the value of ex vivo drug testing to identify novel, clinically actionable therapeutic opportunities. To pilot this in solid tumours we have developed, by conditional re-programming, patient-derived cells (PDCs) from castration-resistant prostate cancer (CRPC) and renal cell cancer (RCC). PDCs are compared with primary tumour tissue by genomic profiling and then subjected to drug sensitivity profiling with 530 approved and investigational oncology drugs. The drugs are plated in five different concentrations spanning a 10,000-fold concentration range on 384-well plates. So far, cell viability has been the main parameter measured but we are now applying automated high-content imaging of hundreds of phenotypic features from drug-treated PDCs. Healthy control cells enable identification of general toxic effects. Intra-patient heterogeneity can be assessed by multiple tumour samplings. High throughput cell-based functional drug testing is conducted in many different ways across laboratories. Hence, harmonization of assay controls and metrics of drug efficacy are needed to enable translation. Correlation of ex vivo and in vivo efficacies need to be demonstrated in large-scale clinical trials in the future.
Here, we generated both benign and malignant PDCs from prostate tissue, as well as renal cell carcinoma tumour regions. We verified their clonal relationship with the uncultured tumour tissue by NGS and performed drug sensitivity testing. The RCC PDCs retained CNAs and driver mutations in e.g. VHL, PBRM1, PIK3C2A, KMD5C, TSC2 genes and showed sensitivity to pazopanib and temsirolimus that inhibit VEGFR/PDGFR/FGFR and mTOR. The individual PDC from different regions in one patient showed distinct drug response profiles, confirming that genomic heterogeneity leads to variability in drug responses
Our aim is to generate molecular profiles and drug testing data using representative PDCs from cancer patient samples to help clinicians in treatment decision and to facilitate the early selection of the best drug candidates for clinical development.
Benedikt Kessler graduated from the Swiss Federal Institute of Technology ETH in Zurich, Switzerland in Biochemistry in 1992. He received his PhD in Immunology at the Ludwig Institute for Cancer Research at the University of Lausanne in 1998. He then joined the laboratory of Hidde L. Ploegh at Harvard Medical School in Boston, USA, to study the role of proteolysis in antigen processing and presentation. After three years, he established a research platform in proteomics at HMS. He has then been called to the University of Oxford in the UK, where he currently holds a Professorship in Biochemistry and Life Science Mass Spectrometry at the Target Discovery Institute (TDI). His laboratory is focused on ubiquitin and protease biology with a speciality in mass spectrometry, proteomics and recently in metabolomics. Expertise in his laboratory is also used to define “molecular signatures” in disease processes and accelerate target discovery in translational research.
Targeting the Ubiquitin System for Anti-Cancer Therapy
Ubiquitination controls the stability of most cellular proteins and its deregulation contributes to human diseases. For example, many oncoproteins are subject to ubiquitination-dependent degradation, which is compromised in cancer cells. Deubiquitinases (DUBs) remove ubiquitin from proteins and their inhibition can induce degradation of specific proteins including potentially otherwise undruggable oncoproteins, making DUBs attractive anti-cancer drug targets. A unique multi-lab Industry-Academia Alliance led by CRUK Therapeutic Discovery Laboratories (CRUK-TDL) and FORMA Therapeutics, and in collaboration with four academic centres, has focused on the development of highly specific DUB inhibitors with ubiquitin specific protease 7 (USP7) representing a high priority target. A high-throughput screening campaign targeting USP7 was carried out at FORMA Therapeutics, and lead to the development of a series of novel and potent USP7 inhibitors. Mass spectrometry and crystallography studies reveal that our inhibitors bind within the catalytic domain to the auto-inhibited, apo-form state of USP7, leading to selective inhibition of its deubiquitinase activity. USP7 controls the stability of the oncogenic E3 ligase, MDM2, which is reflected in changes to its substrate, the tumour suppressor p53. Inhibition of USP7 leads to degradation of MDM2 coupled to re-activation of p53 in various cancers.
After completing his Ph.D. in organic chemistry in 1980, Mike has worked in Pharma R&D initially as a medicinal chemist and then as a computational chemist. He joined Glaxo in 1986 and was responsible for helping initially build and then lead the computational chemistry department. More recently he led the biophysics and protein crystallography activities including developing fragments theory and practice in lead identification. His current role is in looking at new technologies to enhance our early drug discovery approaches, particularly to help reduce attrition in drug discovery. Current interests include new methods to better understand target tractability and also drug distribution at cellular and subcellular resolution. Mike is a GSK Senior Fellow and an Adjunct Professor in the chemistry department at Imperial College London.
Scientist, Compound Profiling and Cellular Pharmacology Department
Emilie Bureau graduated from the European School for Biotechnology of Strasbourg (ESBS), France in 2004. She then moved to London to work on leukaemic stem cells at Cancer Research UK and obtained her Ph.D. from University College London in 2008. Since then she has been working as a scientist at LifeArc (formerly MRC Technology) in the Compound Profiling and Cellular Pharmacology department, where she has been involved in a number of small molecule and therapeutic antibody projects, focusing mainly on the areas of oncology and neuroscience. Most of the projects she has worked on over the years involved high content screening and imaging.
Identification of Compounds Leading to TDP-43 Aggregates Clearance and Alternative Splicing Function Recovery Using a Novel High Content Screening Assay
TDP-43 aggregates are commonly found in the brain of ALS, FTLD and some Alzheimer’s disease patients. Although it is not fully understood whether TDP-43 aggregate formation is a protective mechanism or has a detrimental effect, the identification of compounds which induce aggregate clearance at the phenotypic level may help with the understanding of TDP-43 proteinopathies.
In this study, a phenotypic high content imaging assay was used to screen for compounds which promote TDP-43 aggregate clearance, without affecting other cell physiology parameters, regardless of their putative mode of action. The model used is a novel inducible GFP tagged TDP-43 construct containing 12Q/N repeats in HEK293 cells. This construct is sufficient to cause TDP-43 aggregation, sequestration of endogenous TDP-43, TDP-43 splicing loss of function and locomotive defects in a Drosophila model, thus mimicking ALS disease phenotype.
Several chemical clusters have been identified in the primary screen assay which successfully induce aggregate clearance in a dose-dependent manner. The active compounds also restore TDP-43 function as an intronic splicing enhancer of POLDIP3 in a secondary functional assay indicative of on-target effects. Ongoing studies in the Drosophila model indicate that the selected compounds also revert the in vivo phenotype.
Martin has served in a variety of capacities within DMPK, Drug Discovery and more recently Platform Technology and Science since joining GSK in 1983. His Ph.D. focused on evaluating the use of in vitro systems to model metabolic routes and pharmacokinetic parameters. One of his major scientific roles has been to provide DMPK support to Drug discovery scientists and program teams in lead optimisation. Martin has been active across the drug discovery and development matrix with multiple roles including head of Disposition Sciences within the Respiratory Therapy Area. His current role is focused on coordinating a number of scientific approaches to improving candidate quality and reducing attrition in drug discovery. Martin is a GSK Senior Fellow.
Dr. Denise Barrault was appointed Executive Director of NPSC in November 2015. In this position, she implements NPSC’s strategy to align with university and industry partner’s aspirations to deliver benefits to health and the economy.
During her Ph.D., Denise studied insect antibacterial peptides and their role in Onchocerca spp. transmission in Simuliids at IRAD in Cameroon and at the University of Keele. Denise then started her career at Life Technologies as a team leader in the special oligonucleotides production laboratory, where she developed and optimised novel production and purification methods. Denise went on to do postdoctoral studies at the Institute for Immunology and Infection Research (IIIR) at the University of Edinburgh in Andrew Knight’s laboratory, studying antigen presentation in B cells. Moving back to industry Denise joined Lab901 Ltd., the Scottish based microfluidics and laboratory automation company that developed ScreenTape®, when it was a fledgeling start-up (Lab901 is now owned by Agilent Technologies). At Lab901, Denise was a Product Manager and was responsible for ensuring that ScreenTape® products went from concept to market with the customer in mind.
She then joined SULSA as Executive Director in 2010, where she implemented SULSA’s strategy across the six-member Universities in Scotland. Denise was also responsible for the overall management and promotion of SULSA and established new interactions and collaborations with industry, such as the European Lead Factory and the National Phenotypic Screening Centre. Now reporting to NPSC’s Chairman: Prof. Andrew Hopkins, Denise is responsible for the overall management, governance and promotion of NPSC as well as the establishment of new interactions and collaborations with industry.
Director of Operations and Lab Head
Paul holds a BSc degree in Biochemistry and a Ph.D. in Molecular Biology from the University of Sheffield, UK and has over 25 years post-doctoral research experience spanning biochemistry, genetics, cell biology and quantitative imaging. Since 2007 Paul has focused on phenotypic discovery sciences, holding scientific leadership positions in the Drug Discovery Unit in Dundee and the Swedish stem cell company Cellartis. Since 2013 Paul has been heavily involved in establishing the National Phenotypic Screening Centre, helping to obtain funding then in the design and creation of the centre, taking on his current role running the Dundee lab in 2016. Paul serves on the SAB of Axol BioSciences Ltd, is on the Phenomics Discovery Initiative’s Board and Scientific Committee and Theme Advisor (Technology and Analysis) for the Scottish Universities Life Science Alliance.
The Phenomics Discovery Initiative (PDi): Bringing the Best Predicative Disease-Relevant Biology from Academia into the Industrial Drug Discovery Pipeline
The National Phenotypic Screening Centre (NPSC) was created with ~€11M of Scottish Government investment and launched in 2015, with labs in three highly research-intensive UK Universities: Dundee, Edinburgh and Oxford. A key aim of the centre is to redress the balance in drug discovery, moving away from the types of target-centric approaches that have generally shown poor translational efficacy. NPSC is focusing its efforts on advanced phenotypic screening approaches at all levels: developing the most pathophysiologically-relevant assays possible; leveraging the latest developments in biology such as hiPSC/stem cell technology; CRISPR/Cas9; 3D cultures and organoids; implementing multiparametric profiling and data analysis methods as well as facilitating technology advancement.
There is a deep well of biology in the academic and clinical community that remains somewhat untapped and often lacks translational direction. We have formed a public-private consortium which has Janssen as its founding partner (but open to all Pharma/Biotech) called the Phenomics Discovery Initiative (PDi) that allows the pre-competitive de-risking of phenotypic assay development. PDi leverages NPSC’s world class facilities, industry standard operation and extensive global networks to crowdsource and develop the best biology from the academic, clinical and SME community. PDi’s experts select the projects and the NPSC funds their in-house development and validation (using annotated and diversity-based compound libraries) working very closely with the assay proposers throughout. PDi has a growing portfolio of disease-relevant assays. Current projects cover a spectrum of therapeutic areas including oncology and immuno-oncology, dementia and neuropsychiatric diseases, cell stress, infection and immunity. NPSC also is active in driving the technological innovations that will form the basis for the next-generation of phenotypic assays.
Proteome Biochemistry, Division of Genetics and Cell Biology
Massimo Alessio graduated in Biology (1984), and took the Ph.D. in Human Biology (1993). Meanwhile, he was fellow in the Cell Biology laboratory (Turin-University, Italy), and visiting scientist at Dana Farber Cancer Institute in Boston and at the American Red Cross in Rockville (USA), where he developed expertise in tumor immunology, cell biology and protein biochemistry. Then, Dr. Alessio moved to the San Raffaele Scientific Institute in Milan, Italy (2000) as Project Leader developing his expertise in differential proteomics for biomarkers identification and characterization, and for protein post-translation modifications analysis. In 2007 he became Head of the Proteome Biochemistry Unit and was mainly dedicated to neuro- and onco-proteomics studies. In the last years, his interest was dedicated to ceruloplasmin, a ferroxidase that plays a role in iron-homeostasis, in its modifications occurring in neurodegenerative diseases and in its therapeutic use in the rare genetic disease aceruloplasminemia.
Ceruloplasmin Replacement Therapy Ameliorates Neurological Symptoms in a Preclinical Model of Aceruloplasminemia
Aceruloplasminemia is a monogenic disease caused by mutations in the ceruloplasmin gene that result in loss of protein ferroxidase activity. Ceruloplasmin plays a role in iron homeostasis, and its activity impairment leads to iron accumulation in liver, pancreas, and brain. Iron deposition promotes diabetes, retinal degeneration, and progressive neurodegeneration. Current therapies mainly based on iron chelation, partially control systemic iron deposition but are ineffective on neurodegeneration. We investigated the potential of ceruloplasmin replacement therapy in reducing the neurological pathology in the ceruloplasmin-knockout (CpKO) mouse model of aceruloplasminemia. CpKO mice were intraperitoneal administered for 2 months with purified human ceruloplasmin that was able to enter the brain inducing replacement of the protein levels and rescue of ferroxidase activity. Ceruloplasmin-treated mice showed amelioration of motor incoordination that was associated with diminished loss of Purkinje neurons and reduced brain iron deposition, in particular in the choroid plexus. Computational analysis showed that ceruloplasmin-treated CpKO mice share a similar pattern with wild-type animals, highlighting the efficacy of the therapy. Therefore, our data suggest that enzyme replacement therapy may be a promising strategy for the treatment of neurological pathology in aceruloplasminemia. Waiting for a purified ceruloplasmin product administrable for therapeutic purposes, we are currently set-up a provisional para-enzyme replacement therapy on aceruloplasminemia patients by using transfusion of fresh frozen plasma from donors selected for a physiological high-ceruplasmin content; the aim is to reach a post-transfusion ceruloplasmin level similar to one of heterozygote subjects that do not show the disease.
Professor of Microbiology
Mathias Uhlén received his Ph.D. at the Royal Institute of Technology (KTH), Stockholm, Sweden in 1984. After a post-doc period at the EMBL in Heidelberg, Germany, he became professor in microbiology at KTH in 1988. His research is focused on protein science, antibody engineering and precision medicine and range from basic research in human and microbial biology to more applied research, including clinical applications in cancer, infectious diseases, cardiovascular diseases, autoimmune diseases and neurobiology. His research has resulted in more than 600 publications
Head of Unit
Dr. Max Lemke is the Head of Unit for Technologies and Systems for Digitising Industry in Directorate General CONNECT of the European Commission. He has a leading role in developing and coordinating the strategy for the Digitising European Industry strategy. In the European Commission’s Research and Innovation Programme HORIZON 2020, Dr. Lemke is responsible for the areas embedded and cyber-physical systems, advanced computing, and ICT for manufacturing. He is co-responsible in CONNECT for the Joint Technology Initiative ECSEL (Electronic Components and Systems for European Leadership) and the Public Private Partnership Factories of the Future. In the latter context, he has gradually built the I4MS initiative (ICT Innovation for Manufacturing SMEs). He is particularly devoted to establishing a pan-European network of digital innovation hubs covering all of Europe and to strengthening European leadership on digital industrial value chains and platforms.
Dr. Lemke has worked in various areas in the European Commission Research and Innovation Programmes since 1995. Before joining the Commission, Max has worked in research and industry in Germany, the US, and the UK. With a Doctorate in Natural Sciences, he has a scientific background in numerical mathematics, parallel computing, and software engineering.
Senior Lab Manager
Dr. Louise Berg works at the Karolinska Institutet, Stockholm, and coordinates the establishment of experimental platforms utilizing primary cells from patients with chronic inflammatory diseases within the IMI-funded program ULTRA-DD run by the SGC. The primary aim of these platforms is to screen small molecules and blocking antibodies for effects on cellular mechanisms important in the pathogenesis of the diseases studied, including SLE, myositis, systemic sclerosis and inflammatory bowel diseases. Dr. Berg has a background in cellular immunology, with focus on immune phenotyping in rheumatoid arthritis and NK cell function in human viral disease.
The presentation will include a description of the experimental platforms used, immune mechanisms involved in the pathogenesis of the diseases we study, and results from the screening of 30-50 inhibitory compounds using these platforms. The majority of these compounds target epigenetic regulators and protein kinases. The discussion will focus on how we define compound effects and how we validate such findings. In addition, the relevance of setting up patient-derived assays early in the drug discovery process will be discussed, and how to run collaborations between the pharmaceutical industry and academic researchers, including access to clinical sample and expertise.
Discovery Biology Director
Giovanna Bergamini is Discovery Biology Director at Cellzome, a GSK company at the European Molecular Biology Laboratory (EMBL) campus in Heidelberg. She leads numerous collaborations across different GSK therapeutics areas focusing on the characterization of small molecules mode of action and on the development of translational systems. Dr. Bergamini has led drug discovery programs in the inflammation therapy area and directed screening and immunobiology groups. She has established numerous academic collaborations, more recently in imaging and chemical biology areas.
Intracellular Drug Bioavailability: a New Predictor of Transport and Metabolism Dependent Drug Disposition and Intracellular Target Engagement
A thorough understanding of the molecular mechanisms underlying small molecules effects in the cellular and organ context can greatly impact the success of drug discovery efforts. The comprehensive characterization of drug-proteins interactions can provide evidence of the target-dependency of the observed effects as well as identify potential hazards. In this presentation, newly methods developed to characterize the drug interactome in live cells will be discussed. Examples of applications of these technologies at different drug discovery stages will be described with a focus translational approaches to measure target engagement.
Assistant Professor at the Cancer Therapy Group
Jordi Carreras Puigvert is a M.Sc. in Biotechnology from the Universitat Autonoma de Barcelona. He holds a Ph.D. by the University of Leiden, the Netherlands, where he specialized in large RNAi-based screens studying the DNA damage response in both mammalian cells and c. elegans. In 2013, he was awarded a Marie Curie Intra European Fellowship to join Prof. Thomas Helleday lab at the Karolinska Institutet, in Stockholm, Sweden, and he is currently Assistant Professor at the Cancer Therapy Group, also at Karolinska Institutet, lead by Prof. Oscar Fernández-Capetillo, focused on cell-based high-throughput phenotypic screens for drug discovery.
Drug Screening for Novel Therapies Against Amyotrophic Lateral Sclerosis (ALS)
ALS is a neurodegenerative disease characterized by the loss of motor neurons leading to death within 2 to 5 years after diagnosis, and it has currently no cure. A recent breakthrough points at a hexanucleotide repeat expansion in the non-coding region of the C9ORF72 gene, as a major cause of ALS. These repeats undergo RAN (repeat-associated non-ATG) translation, producing a number of small toxic di-peptides that accumulate in nucleoli. Our laboratory at the Karolinska Institutet focuses on the use of high-content/throughput screening (HCS), and aims to delve deeply into these technologies for the discovery of novel compounds of biomedical interest, with a particular interest on ALS. We have successfully developed a HCS protocol to screen for compounds that diminish the toxicity of one of the ALS-related di-peptides (PR20). Among 4300 medically available compounds, we identified modulators of PR20-mediated toxicity in various systems, including motor neurons and developing zebrafish.
Dr. Patrick Courtney MBA has 20 years’ industrial experience in the development of technology R&D and marketing for the scientific instruments, as a director at PerkinElmer, as well as at Sartorius and Cap Gemini. He leads the European working group on Laboratory Robotics with the European Commission’s AI/Robotics Programme. He is a member of the board of directors of SiLA (Standards in Laboratory Automation) and sits on the Advisory board of the projects AdaLab (Adaptive Automated Scientific Laboratory) and ROAR (Rapid Online Analysis of Reactions). He holds a Ph.D. in Molecular Biology/Engineering, and previously carried out research in AI and Computer Vision, has 100 publications and named as inventor on ten patents.
Scientist at the Princess Margaret Cancer Centre
Dr. Benjamin Haibe-Kains is Scientist at the Princess Margaret Cancer Centre (PM), University Health Network, and Assistant Professor in the Medical Biophysics and Computer Science departments of the University of Toronto. Dr. Haibe-Kains earned his PhD in Bioinformatics at the Université Libre de Bruxelles (Belgium). Supported by a Fulbright Award, he did his postdoctoral fellowship at the Dana-farber Cancer Institute and Harvard School of Public Health (USA). He started his own laboratory at the Institut de Recherches Cliniques de Montréal (Canada) and moved to PM in November 2013. Dr. Haibe-Kains’ research focuses on the integration of high-throughput data from various sources to simultaneously analyze multiple facets of carcinogenesis. In particular, Dr. Haibe-Kains and his team are analyzing high-throughput (pharmaco)genomic datasets to develop new prognostic and predictive models and to discover new therapeutic regimens with the aim to significantly improve disease management. Dr. Haibe-Kains’ main scientific contributions include several prognostic gene signatures in breast cancer1–3, subtype classification models for ovarian and breast cancers4–6, genomic predictors of drug response in cancer cell lines7–11, as well as integrative drug taxonomy12. Dr. Haibe-Kains co-founded the MAQC Society to promote reproducible research in life sciences (maqcsociety.org).
Consistency Analysis of Pharmacogenomic Screens
One of the main challenges in precision medicine is to predict whether a patient will benefit from a given therapy. In this context, it is crucial to develop computational models predictive of therapy response based on molecular features from diseased tissues. Such models could be used to assist clinicians in their decision process and consequently improve disease management. However, testing the effect of drugs in clinical trials is lengthy and costly. Large-scale drug screening in cell lines (in vitro) has recently been used to generate a large amount of molecular data related to drug response. These pharmacogenomic studies hold great promises in identifying biomarkers predictive of therapy response in model systems, which could be further translated into clinical settings. However, the discovery of predictive biomarkers in vitro has proven to be extremely challenging. We showed that this is partly due to inconsistencies in drug response data, leading to irreproducible gene-drug associations across datasets. However, our findings originating from the comparison of two independent large-scale pharmacogenomic screens, Genomics of Drug Sensitivity in Cancer (GDSC) and Cancer Cell Line Encyclopedia (CCLE), were recently contradicted by the GDSC and CCLE investigators who recently reported reasonable agreement of pharmacological phenotypes and molecular predictors of drug response. Reanalyzing the authors’ published methods and results, we found that their analysis failed to account for variability in the genomic data and more importantly compared different drug sensitivity measures from each study, which substantially deviates from our more stringent consistency assessment. Another study from Genentech compared the GDSC and CCLE data to their own datasets and support strong agreement between these datasets although they found the pharmacological assay used in GDSC to be less reliable. We have updated our comparison of the most updated genomic and pharmacological data from these studies to shed light on the (in)consistency in pharmacogenomic studies. Our experience illustrates the importance of unified analytical platforms, data and code sharing in bioinformatics and biomedical research, as the data generation process becomes increasingly complex and requires high level of replication to achieve robust results.
Chief Technology Officer and a Co-Founder
Daniel Levner, Ph.D. is the Chief Technology Officer and a Co-Founder of Emulate, Inc. He joined Emulate’s founding team while at Harvard’s Wyss Institute for Biologically Inspired Engineering. There, Dr. Levner led the advanced engineering team responsible for developing Emulate’s Organs-on-Chips platform as well as the creation of a substantial body of intellectual property around this technology. Dr. Levner played a key leadership role in the formation of Emulate, and he was particularly instrumental in formulating approaches to foster close and effective collaboration between biologists and engineers, which is crucial to Emulate’s multidisciplinary work. Prior to Emulate, Dr. Levner worked with world-renowned Harvard geneticist Professor George M. Church in programs related to medical diagnostics, DNA/RNA sequencing and synthesis, and multiplexed molecular visualization. As an entrepreneur, Dr. Levner co-founded an artificial intelligence/data sciences medical-diagnostics company, and earlier in his career, an optical telecommunications company. Dr. Levner received his Ph.D. in electrical engineering from Stanford University and an MS in aeronautics and astronautics, also from Stanford. He has contributed to numerous publications and presentations, as well as more than 40 issued and pending patents.
Organs-on-Chips: A Platform for Drug Development and Disease Modeling
Organ-Chips – such as the Lung-, Liver-, Brain- and Intestine-Chips – are micro-engineered systems that display physiological functions consistent with human in vivo. Each Organ-Chip is composed of a clear flexible polymer about the size of an AA battery that contains hollow channels lined by living human cells; these cells are cultured under continuous flow and mechanical forces, which recreate key aspects of the in vivo cellular microenvironment. We have found that cells cultured within the engineered 3D microenvironments of Organ-Chips go beyond conventional in vitro models, making Organ-Chips more predictive of in vivo physiology. Accordingly, Organ-Chips enable the study of normal physiology, pathophysiology, and mechanisms of action or toxicity in an organ-specific context.
In this presentation, we discuss recent advances in the application of Organ-Chip systems that are relevant to drug development and disease modeling. Particularly, we highlight studies from collaborative efforts across our Human Emulation System with various academic and industry partners to demonstrate the utility of the system and qualify it as a more predictive and human-relevant alternative for efficacy, safety, and mechanistic studies.
Professor for Pharmaceutical Chemistry
Stefan Laufer, is Professor for Pharmaceutical/Medicinal Chemistry at Tuebingen University. He received his degrees from Regensburg University. After 10 years in Pharmaceutical Industry (Head Drug Research, R&D Director Merckle GmbH) he joined in 1999 Tuebingen University as Chairman Pharm./Med. Chemistry. His research interests are anti-inflammatory and cancer drug discovery with various eicosanoid (COX-1,2,3, LOXs, mPGES1, cPLA2) and protein kinase targets (p38, JAKs, JNKs, CK1d, mtEGRFs) . Three compounds from his lab entered clinical development phases. Dr. Laufer chairs the ICEPHA (Interfaculty Center for Pharmacogenomics and Drug Research) and TüCADD, Tuebingen Center for Academic Drug Discovery. As part of this work, a proprietary kinase inhibitor collections is established (TüKIC, 7000 cpds).
He authored more than 365 publications, 14 books/bookchapters and is inventor in 42 patent families.
Covalent Inhibitors Re-Invented
Covalent Inhibitors belong to the oldest and most successful drugs. Prominent examples are e.g. Acetylsaliclic Acid, ß-Lactone Antibiotics or Gastric Proton Pump Inhibitors. A major breakthrough in cancer therapy of the last decades was targeted therapy with protein kinase inhibitors. Still unmet needs in this field are target residence time, selectivity and rapid development of target kinase mutations. A very seminal approach to address these issues was described 2013 by Liu et al. “Targeting the Cysteinome“: We applied this strategy to unsolved problems in the field of JAK3, JNKs and mutant EGFR kinases. JAK3 signaling is a key driver in the development of lymphoid cells and modulation of immune response. Due to its isolated expression in lymphocytes a selective JAK3 inhibitions is considered to be a promising strategy for the development of new immunosuppressant drugs. Via a covalent-reversible inhibition approach we were able to develop new highly potent JAK3 inhibitors with high isoform specificity as well as an outstanding kinome wide selectivity. A novel binding mode was observed in the x-ray structure.
Peter Kirkpatrick studied for a BA at the University of Cambridge, United Kingdom, specializing in chemistry. He stayed in Cambridge for his Ph.D. and post-doctoral research, investigating the biosynthesis and mode of action of vancomycin-group antibiotics in the group of Dudley Williams. He joined the launch team of Nature Reviews Drug Discovery as Associate Editor in 2001, and became Chief Editor in 2004.
Dorothy Hodgkin Research Fellow and a University Research Lecturer, based in the Departments of Chemistry and Radcliffe Department of Medicine
Akane Kawamura, D.Phil, is a Dorothy Hodgkin Research Fellow and a University Research Lecturer, based in the Departments of Chemistry and Radcliffe Department of Medicine at the University of Oxford. After her undergraduate degree in Chemistry, she received her D.Phil in Pharmacology from Oxford. She spent three years in industry as a senior researcher, where she led a number of drug discovery projects across a wide range of therapeutic areas. In 2009 she returned to University of Oxford to work on chemical biology approaches to studying epigenetic regulation. She was awarded a BHF CRE Fellowship in 2012 and a Dorothy Hodgkin Fellowship in 2013. Her group’s research focuses on the biochemical/cellular studies of histone demethylases, the development of chemical probes against epigenetic protein targets, and the development of peptide-based target validation approaches.
Cyclic Peptide Tools for Epigenetic Proteins
Post-translational modifications (PTMs) on histone tails are of central importance in regulation of gene expression. Histone PTMs are dynamically modified and recognised by a wide range of epigenetic proteins / enzymes. Abnormal histone modification patterns and dysregulation of epigenetic proteins are implicated in many diseases. Thus, there is significant interest in developing chemical tools to probe the biology and to explore the therapeutic potential of these epigenetic proteins. Metylation of lysines on histones is reversible, and regulated by histone methyltransferases (KMTs) and demethylases (KDMs). KDMs catalyse the removal of methylated lysines on histones. Despite the emerging importance of KDMs in cellular processes and the intense therapeutic interest in relation to diseases, developing chemical tools for KDMs have been challenging.
The talk will focus on our recent work on the development of selective and potent cyclic peptide inhibitors against histone demethylase KDM4A-C. We applied Random non-standard Peptide Integrated Discovery (RaPID) system to screen a diverse set (>1012) of cyclic peptide libraries for KDM4A binding sequences that inhibit enzyme activity. We used structure- and activity-guided modifications to further optimise the cyclic peptides for cellar studies. Our work highlights the utility of the approach for the generation of potent, substrate competitive and selective KDM inhibitors, and more generally, for developing inhibitors targeting challenging protein targets.
Robert received his Ph.D. in Biochemistry from the Leiden University Medical Center on the study of Oncogenic cell transformation. He subsequently moved to Stanford University (USA) to do his Post Doc studying neural stem cells. Upon his return to the Netherlands, he continued the study of stem cells in the group of Prof Hans Clevers at the Hubrecht Institute in The Netherlands.
In the group of Hans Clevers, he was part of the team that developed the breakthrough technology that allowed the expansion of adult stem cells. The so-called Organoid Technology became the basis of the non-profit company ‘Hubrecht Organoid Technology’ (HUB) of which he is currently the managing director.
Organoids: the Next Generation in Vitro Predictive Patient Model
Key to the development of the Organoid Technology was the discovery of LGR5+ intestinal adult stem cells by the lab of Hans Clevers. When provided with the appropriate growth factors, the adult stem cells were found to form a polarized epithelium in which stem cells and their off spring such as differentiated cells maintain their natural hierarchical and functional role. Importantly, organoids proved to be both genetically and phenotypically stable during cell culture. After the discovery of the method for intestinal cells we developed methods for many other organs such as liver, lung and pancreas.
HUB (Hubrecht Organoid Technology), a non-profit company that was founded based on the proprietary Organoid Technology developed in the Clevers lab, implements the Organoid Technology in pre-clinical drug development as well as a clinical platform for patient stratification in clinical trials, biomarker discovery and as a companion diagnostic.
Director of the Laboratory for Epigenetics and Environment
Jörg Tost received his Ph.D. in genetics from the University of Saarbrücken (Germany) in 2004 devising novel methods for the analysis of haplotypes and DNA methylation patterns. After a postdoctoral stay in the technology development department of the Centre National de Génotypage (CNG, Evry, France), he led the Epigenetics groups from 2006-2012, before becoming Director of the Laboratory for Epigenetics and Environment at the Centre National de Génotypage, now called the Centre National de Recherche en Génomique Humaine (part of the CEA-Institut de Biologie Francois Jacob). The laboratory is involved in the development and application of technologies to analyze DNA methylation, miRNAs and other epigenetic modifications quantitatively at high resolution at target loci and genome-wide using state-of-the-art sequencing technologies as well as the development of bioinformatic tools for the processing of such data. While initially focusing on the analysis of DNA methylation patterns implicated in tumorigenesis, the laboratory has extended the analysis to immune-related and neurodegenerative diseases with large-scale projects investigating DNA methylation and miRNA expression patterns in Parkinson’s Disease, Progressive Supranuclear Palsy (PSP), and Multiple System Atrophy (MSA). Jörg Tost has an H-index of 38 and is author or co-author of 145 publications of which 130 have appeared in Medline-listed journals, and is the editor of a book entitled “Epigenetics” (Horizon Scientific Press, 2008) and the 2nd and 3rd Edition of « DNA methylation protocols » and “pyrosequencing “ in the Methods of Molecular Biology series (2009, 2015, 2017) and senior editor of the journal “Epigenomics” (Future Sciences, IF 4.6).
Emerging Technologies for Genome- and Epigenome-Wide Analyses in Ageing and Degenerative Diseases
Laboratory for Epigenetics & Environment, Centre National de Recherche en Génomique Humaine, CEA – Institut de Biologie François Jacob, Evry, France
The technical revolution of massively parallel sequencing, which allows the interrogation of genetic and multiple epigenetic modifications using the same analytical technologies, together with advances in miniaturization and single cell technologies as well as the development of advanced low-cost high-throughput genotyping technologies has spurred our knowledge on genetic variation and gene regulatory mechanisms involved in ageing and neurodegenerative diseases. Epigenetic modifications add additional layers of information on top of the bare genomic sequence thereby dramatically extending the information potential of the genetic code. The field has gained great momentum in recent years as it has become clear that epigenetics plays a key role in normal development, ageing as well as in disease. DNA methylation occurring at CpG dinucleotides is probably the best-studied epigenetic modification due to the extensive mapping of DNA methylation patterns in different diseases. While initially, epigenetic research has focused on the analysis of epigenetic alterations in cancer, research in recent years has demonstrated that alterations are also present in nearly all complex diseases including neurodegenerative and other brain-related diseases. Analysis of DNA methylation in brain tissues is complicated by the fact that these contain also considerable levels of 5-hydroxymethylation, an epigenetic modification with distinct regulatory roles, but indistinguishable from DNA methylation using standard technologies. In this presentation, I will review key facts on the involvement of epigenetic modifications in ageing and neurodegenerative diseases and summarize the lessons learned from a number of now published epigenome-wide association studies (EWAS) and detailed analysis of the miRnome in neurodegenerative diseases. I will highlight some of the challenges when analyzing epigenetic modifications such as the cell-type specificity of epigenetic modifications and the resulting necessity for cell sorting disease relevant cell-types to improve the detection of disease-associated changes. Using both our own and published data, I will show the potential of epigenetic changes for various clinical applications: to understand the pathophysiology of the disease, as diagnostic tools as these changes are occurring often early during disease development when patients are still asymptomatic, or possibly predict the success of therapy at an early time point. In parallel, epigenetic therapy and epigenome engineering using the CRISPR/dCas9 approach have recently made great progress. It is now feasible to modulate epigenetic modifications at a specific locus allowing for the first time to assess the functional relevance of epigenetic changes, and this approach might be of great potential relevance for complex and chronic diseases without targetable mutations, but profoundly altered epigenetic landscape such as inflammatory and neurodegenerative diseases. While the systematic investigation of epigenetic changes is still in its infancy, these data will ultimately lead to advancements in detecting, treating and preventing neurodegenerative diseases and spur evolvement a systematic precision medicine strategy.
Brinton received her Ph.D. in 2012 from KTH Royal Institute of Technology in Stockholm, Sweden in organic synthesis. She then moved to the Broad Institute with Stuart Schreiber for a postdoc in chemical biology. Here she worked on developing methods to integrate small-molecule sensitivity data with cellular and genetic features.
In 2015 Brinton moved to Karolinska Institute at the Chemical Biology Consortium Sweden and currently, Brinton is involved in translational medicine with the Olli Kallioniemi group. Here she focuses on developing novel readouts of drug response on patient-derived cell models. These results are then integrated with other “omics” profiles of the same patient with the hope of providing insight into more efficacious therapies for individual patients.
Cellular Thermal Shift Assay (CETSA): Developments in Data Interpretation and Detection
A prerequisite for generating successful drugs is identifying a small molecule that effectively binds the desired target in the complex environment of a living system. Drug binding with its target protein has typically been difficult to monitor in physiologically relevant models. One recent technique for quantifying drug–target engagement is the cellular thermal shift assay (CETSA), in which ligand-induced protein stabilization is measured after a heat challenge. Building on this method, we established a high throughput, AlphaScreen® assay for detection of remaining soluble p38α (MAPK14), allowing for the simultaneous generation of multiple isothermal dose response fingerprints (ITDRF CETSA) for this protein. Using this platform we outline a framework for delineating the affinities and selectivities of drug-target interactions by varying the temperature and duration of the heat challenge. For five inhibitors investigated in this study, linked thermodynamic equilibria and irreversible protein aggregation adequately describe the observed data. On the other hand one for one inhibitor a long-off rate leads to distinct frozen equilibrium behavior, a phenomenon that is importantly also reproduced in live cell measurements. We further describe a CETSA protocol in live A431 cells for p38α (MAPK14), where remaining soluble protein is detected in situ using high-content imaging. We validate this assay concept using a number of known p38α inhibitors and further demonstrate the potential of this technology for drug discovery by performing a small pilot screen for novel p38α binders. Notably, this protocol creates a workflow that is amenable to adherent cells in their native state and yields spatially-resolved, target-engagement information measurable at the single-cell level.
Senior Group Leader
Shantanu Singh is a Senior Group Leader in the Imaging Platform at the Broad Institute. He leads a data science group that develops computational and statistical methods to create fingerprints of genes, chemicals and diseases from microscopy images of cells. Using assays like Cell Painting that capture a broad range of their morphological properties, cellular populations are characterized at single-cell resolution to discover similarities and differences among treatments. This work has the potential to transform how both the targets and therapies for disease are identified.
After completing his Ph.D. at Ohio State in Computer Science, Shantanu joined the Imaging Platform, inspired by the group’s vision to make cell morphology as computable as genomes. He has previously worked in research groups at Mercedes-Benz R&D, GE Global Research, and Lawrence Livermore National Laboratory, where he applied computer vision and machine learning techniques to a wide range of problems in road safety, cell biology, and geospatial imaging.
Information in Images: Targeting Diseases and Characterizing Compounds Via CellProfiler and Cell Painting
Images contain rich information about the state of cells, tissues, and organisms. We work with biomedical researchers around the world to extract quantitative information from images, particularly in high-content screening experiments involving physiologically relevant model systems. As the biological systems and phenotypes of interest become more complex, so are the computational approaches needed to properly extract the information of interest; we continue to bridge the gap between biologists’ needs and the latest in computational science (e.g., deep learning).
Beyond measuring features biologists specify, we extract more from images through profiling experiments using the Cell Painting assay, where thousands of morphological features are measured from each cell’s image. We are working to harvest similarities in these “profiles” for grouping genes, identifying the functional impact of cancer-associated alleles, discovering disease-associated phenotypes, and identifying novel therapeutics. Ultimately, we aim to make perturbations in cell morphology as computable as genomics data.
All novel algorithms and approaches from our laboratory are released as open-source software, including CellProfiler, CellProfiler Analyst, and Cytominer.
Steve carried out his Ph.D. at the MRC National Institute for Medical Research (NIMR) in the division of Developmental Biology (Lab of Dr. Derek Stemple). He worked as a postdoctoral scientist with Prof Austin Smith FRS at the Universities of Edinburgh and latterly Cambridge. He established his own independent laboratory in 2010 at the new UCL Cancer Institute, before relocation in 2013 to the MRC Centre for Regenerative Medicine and the Cancer Research UK Edinburgh Centre at the University of Edinburgh.
Steve is currently holder of the prestigious Cancer Research UK Senior Research Fellowship. In 2017 he was promoted to full Professor (Chair of Stem Cell and Cancer Biology). His laboratory continues to study the molecular and cellular mechanisms that regulate neural stem self-renewal and differentiation, and how these operate in the context of human brain tumours. He has interests in cell-based phenotypic screening for drug discovery; this is an area where the new technologies emerging from stem cell biology, genome editing and mammalian synthetic biology are opening up tremendous new opportunities for discovery.
Accelerating Glioblastoma Drug Discovery: Convergence of Patient-Derived Models, Genome Editing and Phenotypic Screening
Patients diagnosed with glioblastoma (GBM) continue to face a bleak prognosis. It is critical that new effective therapeutic strategies are developed. GBM stem cells have molecular hallmarks of neural stem and progenitor cells and it is possible to propagate both non-transformed normal neural stem cells and GBM stem cells, in de-fined, feeder-free, adherent culture. These primary stem cell lines provide an experimental model that is ideally suited to cell-based drug discovery or genetic screens in order to identify tumour-specific vulnerabilities. For many solid tumours, including GBM, the genetic disruptions that drive tumour initiation and growth have now been catalogued. CRISPR/Cas-based genome editing technologies have recently emerged, transforming our ability to functionally annotate the human genome. Genome editing opens prospects for engineering precise genetic changes in normal and GBM-derived neural stem cells, which will provide more defined and reliable genetic models, with critical matched pairs of isogenic cell lines. Generation of more complex alleles such as knock-in tags or fluorescent reporters is also now possible. I will discuss the convergence of these advanced technologies (iPS cells, neural stem cell culture, genome editing and high content phenotypic screening) and how they herald a new era in human cellular genetics that should have a major impact in accelerating glioblastoma drug discovery. I provide examples of our lab’s progress in generating and using such GBM models for cell-based phenotypic drug discovery (PDD).
Head of Protein Crystallization
Alexey Rak got his M.Sc in Biology and Genetics, and in Biochemistry. He then completed Ph.D.s in Biochemistry and Biophysics working on protein biosynthesis machinery characterization. He did his PostDoc and then held a Group Leader position at Max-Planck Institute for Molecular Physiology in Germany working in the field of vesicular membrane trafficking. For this work, he was awarded several honours including European Young Investigator Award in 2004. Since 2007 Alexey joined Sanofi as head of protein crystallization in Paris where he has developed new biophysical methods and applications for biomolecular interaction characterization working on a number of modalities across therapeutic areas that enabled the lead discovery of challenging protein targets. Since 2014 he is heading BioStructure and Biophysics department at Integrated Drug Discovery in Sanofi.
Integrating Novel Biophysical Approaches in the Early Discovery Pipeline
Abstract: Fragment-based lead discovery has proved to be an effective alternative to high-throughput screenings in identifying chemical matter that can be developed into robust lead compounds. The search for optimal combinations of biophysical techniques that can correctly and efficiently identify and quantify binding can be challenging due to the physicochemical properties of fragments. In order to minimize the time and costs of screening, optimal combinations of biophysical techniques with maximal information content, sensitivity, and robustness are needed. Here we present an approach utilizing automated microscale thermophoresis (MST) affinity screening to identifying fragments. MST in concert with nanoDSF proved to identify multiple hits that were confirmed by X-ray crystallography but not detected by orthogonal methods. Furthermore, MST and nanoDSF also provided information about ligand-induced aggregation and protein denaturation. The technique delivered a large number of binders while reducing experimentation time and sample consumption, demonstrating cost- and time-effectiveness of MST to execute and maximize the efficacy of fragment screening campaigns
The audience will gain further insight into:
Head Integrated Drug Discovery Germany
Dr. Alleyn Plowright obtained his Ph.D. in organic chemistry with Professor Gerald Pattenden at the University of Nottingham, UK in 1999, and continued with postdoctoral studies in chemical biology with Professor Andrew Myers at Harvard University, USA. In 2002, Alleyn joined AstraZeneca in the UK and in 2008 became Associate Director Medicinal Chemistry at AstraZeneca Sweden leading the Lead Optimisation section delivering programs to the clinic. In 2012, Alleyn took on the role of Senior Principal Scientist and Project Leader in the Cardiovascular and Metabolic Diseases Innovative Medicines unit leading multidisciplinary research and taking new projects into and through the drug project portfolio. In 2017 Alleyn moved to Sanofi as Head Integrated Drug Discovery Germany leading a cross-disciplinary research unit driving projects from target validation through to pre-clinical development. His current research interests include Drug Design, Phenotypic Drug Discovery and diverse chemical approaches to treat metabolic, cardiovascular and immunological diseases.
Technology Enhancing Early Drug Discovery – Applications with iPS-Derived Cells, Phenotypic Screening and Peptide Drug Discovery
As science and technology rapidly advance, our understanding of biological processes and our ability to probe and modulate these systems are increasing. One area is the application of cross-disciplinary phenotypic discovery to investigate emerging biology as a powerful approach to discover new biological targets and molecules. The increased access to patient-derived cells or tissues and developments in induced pluripotent stem (iPS) cell technology coupled to more complex cellular systems such as three-dimensional cultures or organs on a chip is providing opportunities for more disease-relevant screens to ultimately discover human disease relevant biological targets and hit molecules.
Exciting novel biological targets are being discovered where modulation may enable new therapeutic options for many diseases. These targets include growth factor receptors, protein-protein and protein nucleic acid interactions, which are often refractory to classical small molecule approaches. Other types of molecules, or modalities, can therefore be used to address these targets. One class of these molecules are peptides, which are often highly selective and potent signalling molecules. However, the inherent instability of peptides in plasma leading to a short half life after dosing has limited the broader application of peptide-based drugs. A range of approaches are now being explored and applied to extend the half life of bioactive peptides including the use of more stable, natural peptidic frameworks and utilising other modalities, such as small molecules, conjugated to peptides to enhance their properties. Once a bioactive peptide with the desired biological properties has been discovered, many challenges remain including optimising the physicochemical and biophysical properties of the peptide-based molecules to allow effective development.
The development of new technologies are enabling advancements in both phenotypic drug discovery and the utilisation of New Modalities creating new opportunities for scientists to innovate and discover impactful medicines to treat patients. This talk will illustrate these different approaches in emerging areas of biology such as discovering novel regenerative molecules in the arena of heart failure, molecules which modulate the sphingolipid pathway and reduce glycosphingolipids and applications of New Modalities towards finding new therapies for diabetes and obesity. Applications of these approaches will give a more impactful and successful future to discover new innovations to save patient’s lives.
Chief Operating Officer
Susanne Müller-Knapp studied Human Biology in Marburg Germany followed by a Ph.D. in molecular biology at the Karolinska Institute in Stockholm, Sweden (1997). She then had more than 6 years of postdoctoral training in the area of inflammation and gene regulation at the Karolinska Institute and at the DIBIT San Raffaele Scientific Institute in Milan, Italy.
In 2004 Susanne joined the Structural Genomics Consortium, SGC, in Oxford. The SGC is an international public-private partnership that currently comprises 8 international pharmaceutical companies and a large network of academic and industrial collaborators. Susanne worked at the SGC first as External Research Manager and then Scientific Coordinator. She has been the Project Manager of the Epigenetic Probe Project, which generates tool compounds with defined specificity and selectivity for epigenetic targets and the cell-based assay group at the SGC in Oxford testing the cellular activity of the in vitro characterised tool compounds. In her role as Chief Operating Officer at the SGC Frankfurt Susanne is now coordinating several probe programs including the global SGC kinase chemical probe program and the donated probe program, which makes probes available from the pharmaceutical partners of the SGC.
Associate Director – Mechanistic Biology & Profiling
Thomas Lundbäck is Associate Director within the global Discovery Sciences organisation at AstraZeneca, providing reagent, assay development and screening services. Dr. Lundbäck also serves as an affiliate of the Karolinska Institutet, supporting the national chemical biology infrastructure in Sweden. He is particularly passionate about the application of biophysical assays in primary cells to enable translation to patients.
I obtained a Degree in Chemistry (Univ. Ramon Llull,1994) and Chemical Engineering (IQS, 1995). After obtaining a Ph.D. in Organic Chemistry (University of Barcelona, 1999) I joined the group of Lewis Kay in Toronto for a post-doctoral stay (University of Toronto, 2000-2004). I was then the recipient of a Ramon y Cajal reincorporation contract at the Parc Cientific de Barcelona (2004-2006) and I currently am a group leader at the Structural Biology Unit of the CIC bioGUNE. My research line focuses of the use of nuclear magnetic resonance (NMR) to the study of biologically relevant proteins and enzymes, paying special attention to the delicate balance existing between protein stability and dynamics. I have published more than 65 papers with a total number of citations (1998-2018) of 2600 and an h-index of 20. I am the Spanish delegate for the trans-domain of the COST program. I have been awarded the prize of the Real Sociedad Española de Química (2004) and the Spanish NMR group prize (2005). I am currently the president of the GERMN and vicepresident of the Spanish Chemical Biology Association.
Repurposing Ciclopirox as a Pharmacological Chaperone for the Treatment of Congenital Erythropoietic Porphyria
Congenital erythropoietic porphyria is a rare autosomal recessive disease produced by a deficient activity in the uroporphyrinogen III synthase, the fourth enzyme of the haem biosynthetic pathway. The disease impacts in many organs can be ill-threatening and currently, there are no curative treatments available. Biochemically, inherited mutations most frequently reduce enzyme’s stability, altering its homeostasis to ultimately decrease the intracellular haem production. Uroporphyrin by-products from the frustrated biosynthesis accumulate in the body, severing the pathology with symptoms like skin photosensitivity and phototoxic disfiguring cutaneous lesions. In here, we demonstrate that the synthetic marketed antimicrobial ciclopirox associates to the enzyme and stabilizes it. Ciclopirox targets the enzyme in an allosteric site, distant from the active centre, not affecting the enzyme’s catalytic role. The drug shows activity in vitro, in cellula and ex vivo, and is able to alleviate most of the clinical signs in a bona fide mouse model of the disease at sub-toxic concentrations, establishing a novel therapeutic intervention line against congenital erythropoietic porphyria, applicable to the majority of the deleterious missense mutations causing this devastating disease.
Head of Core Scientific Facilities and Services
My research has focused on the neurodegenerative field and the understanding of the molecular mechanisms involved in cell function and pathology. After my master degree in Italy, I acquire my Ph.D. at the University of Konstanz. In 2000 I joined the Toxicology Unit of the MRC in Leicester where I was working in the emerging field of high content imaging. In 2004 I moved to the Max Plank Institute for Cell Biology and Genetics in Dresden where I was involved in the establishment of the HCS Facility and in the development of innovative cell-based assays. In 2009 I joined the German Centre for Neurodegenerative Diseases, where I have the position of Head of Core Scientific Facilities and Services. My actual focus is to work at the edge of biology, computational science and technology to develop new methods to be applied to cell biology and early drug discovery for neurodegenerative diseases.
High-Content Screening: Use the Phenotype to Unravel Neurodegenerative Diseases
Phenotypic screenings (PS) are an essential tool for drug discovery and for deconvolution of the mechanistic machinery of pathways of interest. However a substantial challenge in PS is the identification of the molecular targets that govern a phenotypic response of interest. The use of computational methods for identification of target and mechanism of action is an approach that can support the analysis of phenotypic screening campaign. Here we show our development to the computational analysis of data generated by high content screening for the NLRP3 inflammasome.
Using a systems biology approach, we first defined a ‘biological spaces’ i.e. the network representations of the biological entities know to be part of the biological process under investigation, in this case the inflammasome.
Second, we defined our ‘chemical space’ network. The ‘chemical space’ network is generated by combining the quantitative data for the hits generated in the PS (using a chemogenomic library) with the data gathered from available online databases on effective compounds and their bioactivities, thus representing the influence of the chemical compounds on the biological process under investigation.
By merging the chemical and biological spaces the resulting bio-chemical network then shows how and where the different compounds affect the biological process, giving us the opportunity to identify regulatory proteins and pathways. This leads to insights into the biological processes involved and the possibility to predict additional and novel targets to influence the system.
Our work show that our computational method successfully enable us to analyze and deconvolve data obtained in PS. Our computational pipeline is not only able to analyze hits but also to predict the mechanistic machinery behind the given phenotype and to identify the key targets involved in the mode of action of a given small molecule.
In conclusion we demonstrate that our computational analysis of PS data can identify previously unknown regulatory processes of the biological system being investigated. Additionally, we show here that our analysis can support the drug discovery pipeline and lead to novel target prediction for pharmacological intervention.
Professor in Dosage Form Design at the Department of Pharmacy
Per Artursson is a professor in Dosage Form Design at the Department of Pharmacy, Uppsala University, Sweden where he heads the Drug Delivery research team. He is also Director of the Uppsala University drug optimization and pharmaceutical profiling platform within Science for Life Laboratories. His research aims at understanding drug absorption, distribution, metabolism and elimination (ADME) at the molecular and cellular level in order to deliver drugs more effectively via the oral route. He also investigates the effects of drug transporting proteins on drug disposition and drug interactions. He has published over 200 research articles and reviews is highly cited and has received several international awards for his research.
Intracellular Drug Bioavailability: a New Predictor of Transport and Metabolism Dependent Drug Disposition and Intracellular Target Engagement
Intracellular drug exposure is influenced by cell- and tissue-dependent expression of drug-transporting proteins and metabolizing enzymes. Here, we introduce the concept of intracellular bioavailability (Fic) as the fraction of extracellular drug available to bind intracellular targets, and we assess how Fic is affected by cellular drug disposition processes. We first investigated the impact of two essential drug transporters separately, one influx transporter (OATP1B1; SLCO1B1) and one efflux transporter (P-gp; ABCB1), in cells overexpressing these proteins. We then investigated the impact of the concerted action of multiple transporters and metabolizing enzymes in freshly-isolated human hepatocytes in culture configurations with different levels of expression and activity of these proteins. We observed that Fic was up to 35-fold lower in the configuration with high expression of drug-eliminating transporters and enzymes. We also used Fic to improve the accuracy of in vitro predictions of clinical drug-drug interactions using a series of 10 time dependent inhibitors. Finally, we determined Fic in multiple cellular assays and cell types representing different targets from a number of therapeutic areas, including cancer, inflammation and dementia. We found Fic predicts drug access to intracellular targets and hence pharmacological effect. Further, Fic gives new insights on membrane permeable compounds in terms of cellular potency and intracellular target engagement compared to biochemical potency measurements alone. We conclude that Fic provides a measurement of the net impact of all cellular drug disposition processes on intracellular bioavailable drug levels inside cells. Importantly, no prior knowledge of the involved drug distribution pathways is required, allowing for high-throughput determination of drug access to intracellular targets in highly defined cell systems (e.g., single-transporter transfectants) or in complex ones (including primary human cells). Knowledge of the amount of drug that is locally available to bind intracellular targets provides a powerful new tool for compound selection in early drug discovery. Finally, our most recent studies suggest that Fic has the potential to improve the accuracy of in vitro predictions of clinical drug-drug interactions.
Dr. Nico Lachmann performed his Master of Science at Hannover Medical School, Hannover and Yale School of Medicine, New Haven CT, USA. After receiving his Ph.D. from Hannover Medical School, Germany, the work of Dr. Lachmann is dedicated towards the development of on new cell and gene therapies for rare diseases. After he became an assistant professor in 2015, his lab is aiming to combine current gene therapy techniques with multipotent and pluripotent stem cells in order to generate therapeutic target cells. Given his translational work, he published numerous papers on the hematopoietic differentiation of human pluripotent stem cells. Dr. Lachmann was awarded with different national and international awards, highlighting his ambiguous goal to drive induced pluripotent stem cell-derived macrophages towards clinical translation.
iPSC-Technology: New Avenues for Cell-Based Therapies
In the past years, the view on macrophages has changed dramatically. Nowadays, macrophages are understood as a unique cell type of the hematopoietic system with high plasticity and regenerative potential. Given these specific functions, the presentation of Dr. Lachmann will provide recent insights into the therapeutic use of macrophages, which can be derived from various stem cell sources. In addition, Dr. Lachmann will also introduce the scalable generation of hematopoietic cells from pluripotent stem cells. Introduced in 2006, the technology of induced pluripotent stem cells (iPSC) holds great promise for various fields of modern medicine such as drug screening, disease modelling and new cell-based treatment approaches. Given the potential of iPSC to differentiate also into cells of the hematopoietic lineage, Dr. Lachmann will present a recently developed, continuous hematopoietic differentiation process which is able to produce different hematopoietic cell subsets. Using this technology, Dr. Lachmann will present data on the use of iPSC and iPSC-macrophages for disease modelling and cell-based therapies. For future clinical translational of iPSC-derived cell subsets, Dr. Lachmann will provide an overview on upscaling of macrophage production into industry compatible bioreactor systems and will shed light into the therapeutic use of generated cell types for rare and common diseases.
Peter Horvath (1980) is currently a group leader in the Biological Research Center of the Hungarian Academia of Sciences in Szeged and holds a Finnish Distinguished Professor (FiDiPro) Fellow position in the Institute for Molecular Medicine Finland (FIMM), Helsinki. He graduated as a software engineer and mathematician, and received his Ph.D. from INRIA and University of Nice, Sophia Antipois, France in satellite image analysis. Between 2007 and 2013 he was a senior scientist at the ETH Zurich, in the Light Microscopy Centre. Peter Horvath is interested in solving computational cell biology problems related to light microscopy and is involved in three main research fields; 2/3D biological image segmentation and tracking; development of microscopic image correction techniques; machine learning methods applied in high-throughput microscopy. He is the co-founder of the European Cell-based Assays Interest Group and the councillor of the Society of Biomolecular Imaging and Informatics.
Phenotypic Discovery Using Machine Learning and Image Analysis Methods
In this talk I will give an overview of the computational steps in the analysis of a single cell-based high-content screen. First, I will present a novel microscopic image correction method designed to eliminate vignetting and uneven background effects which, left uncorrected, corrupt intensity-based measurements. I will discuss the Advanced Cell Classifier (ACC) (www.cellclassifier.org), a software tool capable of identifying cellular phenotypes based on features extracted from the image. It provides an interface for a user to efficiently train machine learning methods to predict various phenotypes. We developed the Suggest a Learner (SALT) toolbox, which selects the optimal machine learning algorithm and parameters for a particular classification problem. For cases where discrete cell-based decisions are not suitable, we propose a method to use multi-parametric regression to analyze continuous biological phenomena. Finally, to improve the learning speed and accuracy, we recently developed an active learning scheme which automatically selects the most informative cell samples.
2008 Founded NanoTemper GmbH together with Stefan Duhr
2010 Ph.D. in Biophysics at Ludwig-Maximilians-University Munich
2012 German Innovation Award
2014 German Founders Award
2015 Elected for one of the 40 most promising talents of Germany younger than 40
2017 TOP100 “innovator of the year” in Germany
Innovations in Biophysical Tools: Make Your Users Great (Again)
Biophysical tools are very important in areas like basic research, drug discovery, formulations development and quality. The rise of biologicals and the related biosimilars have boost this importance. What is often forgotten in this area is, that a tool has to be used by the users, the scientist, not the tool developing engineer. To succeed we have put the user, the researcher, back into the focus. In this talk, I will tell you how we achieve this in R&D, production, sales and customer support.
VP of Sales
Sophie Lintermans joined Andrew Alliance in 2015 and is the VP of Sales. Sophie is responsible for driving global sales for Andrew Alliance and growing the client bases. Prior to joining Andrew Alliance, Sophie successfully managed a team of 15 pharmaceutical consultants in Belgium. After, Sophie coordinated the sales activities in Western Canada for ADInstruments where she was recognized for her sales achievements. Sophie earned a Master in Bio-Engineering from the Catholic University of Leuven in Belgium, with an emphasis on molecular biology.
10 Lessons Learnt – Andrew Alliance
10 candid hints built on direct experience during the creation of business relations with large companies in our field, including some (anonymous) real-world stories. A partnership is a business operation made between two or more companies to share some profits: building a common ground of interests for companies with different size is obviously difficult because they have substantially different financial objectives, timelines and risk-taking constraints. However, there are many situations where large companies need the help of smaller companies because of the difficulty in creating innovation at a larger scale – and this creates a significant, mutual incentive for collaboration. We focus on this peculiar David and Goliath relation, by emphasizing that David can claim victory only if Goliath remains alive and happy…but not necessarily vice-versa.
Steve has been excited about Biochemistry after a high school teacher sparked a passion that led to an Undergraduate degree in Biochemistry he extended his studies as a graduate student. Steve prides himself on a pragmatic approach to research which he regards as a way for him to have fun, pay the mortgage and contribute to the discovery of new medicines. This ethos led him into Pharma, through Glaxo and then Roche (U.K.) to a smaller company (Tularik) in California which evolved into big biotech (Amgen) following an acquisition in 2004. After many years at Amgen, Steve left the established corporate world to join a start-up (Flexus Biosciences) in 2013. Flexus was acquired by BMS in 2015. Since that time Steve has been working at Arcus Biosciences (founded in 2015) where a growing team is building up a portfolio of novel immuno-oncology medicines.
PostDoc Research Fellow
Maria Francisca Coutinho is a PostDoc research fellow at the National Institute of Health Doutor Ricardo Jorge in Portugal. Ever since she finished her degree in Biology, in 2007, her scientific activity has been focused in the field of Health Sciences, particularly in the Human Genetics area.
Maria Francisca has been working in Lysosomal Storage Disorders (LSDs), one of the major groups of genetic disorders, affecting both children and adults. Over these years she has actively contributed to the development of new methods for diagnosis/characterization of LSD patients and to the study of the pathophysiological mechanisms of these diseases. Currently, and taking advantage on the practical skills and theoretical background that those previous works have given her, she is working on a fully molecular approach to promote substrate reduction in a subgroup of LSDs, the Mucopolysaccharidoses, as potential therapeutic approach for these disorders, where no solution exists for the neurological phenotype.
Less is More: Substrate Reduction Therapy for Lysosomal Storage Disorders
The concept of enzyme replacement as a potential therapeutic approach to ameliorate lysosomal storage disorders (LSDs) is virtually as old as the concept of LSD itself. In fact, both concepts were established right after the first enzymatic deficiency underlying an LSD was described, and enzyme replacement therapy (ERT) remained the golden standard for LSD treatment for years. Nevertheless, its ineffectiveness to correct brain pathology, together with its high cost and lifelong dependence prompted the search for additional therapeutic approaches, which are currently being investigated: chaperone therapy; gene enhancement and gene therapy. Still, no matter how effective the treatment or cutting-edge the technology used in any of these cases, the underlying rationale is virtually the same: an attempt to provide or enhance the activity of the missing enzyme.
Yet, 20 years now, an alternative approach arose. Its theoretical basis was established in 1996, when Norman Radin came up with an academic prediction that Gaucher disease (GD) patients could also be treated with a drug able to slow the synthesis of glucosylceramide, the lipid that accumulates in this disorder. Unfortunately, the lack of suitable GD animal models made it difficult to adequately test his hypothesis by the time it was published. Still, the grounds were seeded for the appearance of a second line of work on the LSDs therapeutics field, whose aim was to prevent storage not by correcting the original enzymatic defect but, instead, by decreasing the biosynthesis of the substrate that is accumulated. This approach was called substrate reduction therapy (SRT) and will be the major focus of this talk. Special attention will be given to the most recent advances in the field, introducing the concept of genetic SRT (gSRT), which is based on the use of RNA-degrading technologies (RNA interference and single-stranded antisense oligonucleotides) to efficiently promote substrate reduction by decreasing its synthesis rate. In summary, we will review and compare the results from different teams on the use of gene suppression technologies as tools to achieve substrate reduction.
Senior Product Manager
Patrick Pfenninger is the product manager for the Microlab VANTAGE Liquid Handling System, based in Hamilton Bonaduz, Switzerland. In this role, he is responsible for understanding the needs of the scientific community and automation partners, using this insight to influence technology development. Working within the industry for almost 20 years in various roles and positions, he has a profound understanding of liquid handling and associated technologies.
Chief Sales Engineer
In the early part of my career, I developed a deep and rich set of complex problem solving skills by being challenged with new and unique problems every day. Industrial robotics is a field that requires the simultaneous and careful consideration of spatial, software, efficiency, cost, precision, and environmental requirements. In robotics, making connections between disparate technologies is not the exception; it’s the rule. Each application requires an awareness of the available technology and the tacit knowledge that comes with many years of robotics experience to find the best solution.
My best work has always involved teaching, creating, architecting, facilitating, and/or deploying collaborative robot (CoBot) technology.
Cobots and High Availability Laboratory Automation
Over the past 20+ years, laboratory automation systems have ranged from simple, limited functionality devices for the bench top to room-filling systems that resemble something from a car factory. This journey has yielded many improvements in the design, reliability, speed, and user experience of automated systems. This presentation will highlight these points, but the main focus will be how to maximize the availability of a robotic laboratory automation system to the users. The easier it is to run concurrent processes, train new users, install new instruments and work on an automation tool, the more available it is to its users. The purpose of this presentation is to give users the tools to define a laboratory automation system specification with high availability in mind.
Marcel Mossou has experience in Laboratory Automation and Robotics since 1984 when he started working for Zymark a true pioneer in Laboratory Robotics. Since then he translated a wide range of manual laboratory applications in successful automated processes. In 1994 he founded Lab Services BV, focussing on laboratory robotic automation. Since the management buyout in 2017, he works as a Laboratory Automation Consultant and a Lab Services BV Ambassador.
What Have We Learned from 30 Years of Laboratory (Robotic) Automation
The world of laboratory automation is changing rapidly. It has been since the early days.
Innovations follow each other faster and faster. How can you keep up the pace? The presentation will answer questions like; What has changed in the field of laboratory automation since the early 80s? What were the trends? What are the current trends? Can you copy your manual method? May you expect pitfalls during the automation project? How can I stay ahead of my competitors?
Head of Innovation Field Bio-Sensing and Interfaces
Responsible for the overall project portfolio of the bio-sensing and interfaces innovation field as well generating an ecosystem for successful project execution and driving new business opportunities. Zeeshan holds a degree in International Business and Management from Hogeschool van Amsterdam and an EDGE business degree from UCLA Anderson School of Management. He started his career at Millipore Life Sciences in 2007 in the field of OEM Diagnostics and Serum Cell Culture Media business. In 2011 he won an internal innovation campaign and lead a team of 20+ R&D and Marketing and Sales at Performance Materials working on fuel cells for automotive applications which he led from an idea to business in 4 years. Recently he led a think tank on stretchable electronics and has been pivotal in developing the strategy for the bio-sensing and interfaces innovation field. Utilizing his strong network at Merck and external focus on partnerships to build opportunities and deliver new businesses in this area.
Intraprenuership and Building Momentum
Abstract Over the last couple of years there has been an ever increasing amount of start up like ventures and business units pop up in corporate settings. More and more are corporate employees motivated to think and take risks like start ups and pitch their proposals in front of VC like investors / juries. Employees now enjoy the opportunity to secure funding , bring in external partners and make a best case proposal for an idea or project at hand. Navigating the balance of the corporate meeting the start up is often a good learning for how interacting with any partners when you are trying to sell your idea/project should be done. Building momentum internally breeds a mindset that can be extrapolated into selling your value proposition and vision into the market and gaining traction from internal (innovation boards, funding boards in business units,etc) and traditional external VCs as well as partners and customers. In this talk I would like to talk about the various experience and mechanisms that exist to get things moving and get the momentum you need to move forward.
Director Business Sector Liquid Handling and Automation
An entrepreneur with Global Experience in Lab Automation, Business Development since 17 Years. Started in 2000 at CyBio for Support of Global Sales Development and lead the Liquid Handling Business in Asia and Europe for several years. Recently started to form the business sector as a separate field in Analytik Jena in order to develop for future demands as a solution provider for LabAutomation worldwide.
Chair for Translational Neurodegeneration
Dr. Günter Höglinger holds the Chair for Translational Neurodegeneration at the German Center for Neurodegenerative Diseases (DNZE), Munich, and the Technical University of Munich (TUM). He is a Senior Consultant at the Department of Neurology at TUM and heads the Interdisciplinary Clinical Trial Unit at the DZNE Munich.
After completing a Vor-Diplom (equivalent to BSc) in Physics, he received his MD in 2000. From 2000 to 2003, he completed a post-doctoral fellowship at INSERM in Paris. From 2003 to 2007 he completed a clinical neurological training.
Dr. Höglinger’s investigations focus on Parkinson syndromes. His interests include determining risk factors for neurodegenerative disease, molecular mechanisms of neurodegeneration, modern imaging aiming at the identification of disease mechanisms, and improving diagnostic tools in order to develop novel therapeutics.
Dr. Höglinger is Chair of the International Movement Disorders Society-endorsed PSP Study Group and President-elect of the German Parkinson Association.
In 2017, he was a recipient of the Dingebauer Prize from the German Society for Neurology (DGN). He was also a recipient of a Professorship in the Heisenberg excellence program of the German Research Foundation (DFG), and a First Prize winner for ‘Innovative strategies for neurodegenerative disorders’ from the Dr. Walter and Louise Freundlich Foundation.
James O’Brien has 18 years’ experience in Life Science instruments and laboratory automation industry. Starting his career in a university genomic research lab, James later joined industry working in services, sales operations, product management and marketing. As a Vice President at Tecan, James currently leads the Tecan Integration Group which provides customized solutions for the latest laboratory automation challenges. In addition to his primary role, James leads the Business Excellence team to bring transparency to business through data analysis, process and systems. As an American living in Switzerland, James has a strong understanding of US and European markets and firsthand experience of business in Asia.
Having developed my career across a number of lab-based roles, spanning the pharma R&D process, I now lead Business Alignment for GSK’s “Pharma 4.0” team. Our team delivers disruptive improvements and enhanced productivity across Pharma – discovery, development and manufacturing- using Industry 4.0 technologies.
Medicinal Chemistry Consultant
Paul Leeson is a consultant in medicinal chemistry, advising large and small pharmaceutical companies and academia. He has extensive experience, gained in Smith Kline and French, Merck Sharp and Dohme, Wyeth (USA), AstraZeneca, and GlaxoSmithKline, contributing to the discovery of >40 candidates in the cardiovascular, neuroscience, respiratory and inflammation therapy areas. At AstraZeneca, Paul was head of medicinal chemistry at the Charnwood site from 1997-2011, and he led the Global Chemistry Forum, which managed worldwide activities and implemented strategies in hit-to-lead, lead optimisation, prediction, synthesis and outsourced chemistry. He has a special interest in compound quality, recognised in 2014 by the receipt of the Nauta Award from the European Federation of Medicinal Chemistry. Paul holds an honorary professorship at Nottingham University.
Increasing the Probability of Success by Optimising Compound Quality
It has been acknowledged that causes of clinical attrition and development delay include compound-related issues such as toxicity, failure to achieve efficacious exposure, and poor solubility. These issues can all be addressed in the less costly lead optimisation phase. The physical properties of hits, leads and drug candidates are linked to biological activity, pharmacokinetics, and toxicity. Ligand efficiencies are compound quality measures which quantify in vitro biological activity per unit of a physical property, such as size and lipophilicity. While biological targets often require ligands with differing physicochemical properties, approved drugs are almost always amongst the most ligand efficient for their target. Drug discovery projects should select drug candidates from compounds possessing optimal ligand efficiencies.
EXHIBITION – MEET THE SPEAKERS AREA
The *NEW* SLAS Visiting Graduate Researcher Grant Programme allows for North American or European degree-seeking graduate students to conduct short-term doctoral research or participate in a mentored or independent research project at a host institution.
Stop by the Meet the Speakers area in the Exhibition to meet the first recipient of the SLAS Visiting Graduate Researcher Programme, Kelci Schilling.
The SLAS Professional team will be on hand to answer questions on how to apply for this new SLAS Educational Grant.
Everyone is welcome!
Learn more about this new SLAS Education Grant offering at www.slas.org/awards/slas-visiting-graduate-researcher-program
Round Table Breakfast
Thursday, 28 June
From 8:30 – 10:30
SelectScience® is an innovative online publisher within the science industry, providing vital information to scientists around the world through rich content and trusted reviews. The SelectScience team is passionate about promoting scientists and their work, as well as enabling online conversations to help accelerate critical research and scientific excellence. Visit www.selectscience.net
Benefit from this unique 7 min speaking opportunity at the SLAS Agora.
The purpose is to position your company as a thought leader at the designated area in the exhibition hall during a coffee or lunch break. This will guarantee a big audience.
Please note that:
Benefit from this key opportunity to increase your brand visibility and recognition at the entrance of the conference venue.
Limited to 1 company
Benefit from this opportunity to increase your visibility after the conference.
The post show report is a key summary of the conference and will be disseminated through all SLAS communication channels after the event.
Please note that Post Show Report Includes:
Benefit from this unique opportunity to have breakfast with your designated target audience. It is an invitation-only event with themed tables sponsored by relevant companies.
Each sponsor will have access to 1 table of 10 seats, whereby 2 seats are foreseen for company executives and 8 for invitees from the sponsor. SLAS will provide the sponsor the full attendee list out which the sponsor can choose who to invite to their candid discussion during breakfast. SLAS will then invite the preferred invitees on behalf of the sponsor.
Key to have a candid discussion is to propose several inspiring topics to discuss during your breakfast session.
Participating to this debate will give the sponsor:
Please note that
It consists of a big board at the entrance of exhibition hall where we showcase the entire program and give 1 sponsor recognition by putting their logo on it in exclusivity.
The board will be changed every day according to that day’s program
This opportunity will provide a branding opportunity inside and outside the speakers preview room, where all speakers prepare their presentations.
Benefit from this key opportunity to increase your brand visibility and recognition throughout the venue.
This opportunity consists of an original and attractive three dimensional structure with your preferred communication message.
Limited to 4 companies
Benefit from this key opportunity to increase your brand visibility and recognition at the registration hall.
Limited to 1 company – € on demand (Please reach out to the Sponsorship and exhibition manager)
Reach attendees directly from the outside of the venue with your company message on the outside totem. Two totems will be located at the entrance
The passport is a really popular promotion to attract booth traffic.
Each company that opts for this unique item will be included in the SLAS passport. It will be promoted before and during the show. Attendees must visit your booth, learn more about your products upon which they receive a special company stamp.
At the end of the conference, 1 visitor who collected all stamps, will receive a price at the SLAS lounge during an official prize ceremony.
Wednesday, 27 June
12 : 45 – 12 : 52
Thuersday, 28 June
During the Coffee Break
During the Lunch Break
Booth 3×3 m
Booth 3×6 m
Join the editors-in-chief of the SLAS journals for a step-by-step overview of how to design and write scientific research papers more clearly and effectively to improve their chances for publication. Attendees will learn what editors want, what they don’t want, common mistakes, insider tips and how reviewers evaluate manuscripts. Presented by SLAS Discovery Editor-in-Chief Robert M. Campbell, Ph.D. (Eli Lilly & Co.) and SLAS Technology Editor-in-Chief Edward Kai-Hua Chow, Ph.D. (National University of Singapore). All participants are welcome to attend and encouraged to pick up a boxed lunch and soft drink from the Exhibition and bring it to the workshop.
Entrepreneur, Advisor, Keynote Speaker and Author
A serial entrepreneur, advisor, keynote speaker and author, Peter is one of the most sought-after thought leaders on radical innovation, leadership and the impact of all things digital on society and business. He lectures at various business schools such as the London Business School (UK) and MIT in Boston. Peter has founded nexxworks to help organizations become fluid, innovate and thrive in ‘The Day After Tomorrow’.
The lounge area is an ideal way to boost your visibility at the exhibition hall. Participants will be using this area during all breaks to network informally, to have lunch or to enjoy a coffee. During these precious moments, they will constantly be in contact with your brand. Having a lounge area next to your booth is also an ideal way to attract participants close to your booth.
The lounge area includes:
The lounge area can be further customized with a monitor, plants, roll-ups, coffee corner…
It is however not allowed to display any device in the lounge area, this is only possible at a booth.
You can brand the 3 tables with a visual at choice. The visual needs to be sent in format .eps 30 days prior to the opening of the Conference at the latest.
Anton Simeonov is the scientific director of the Intramural Division of Preclinical Innovation at the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH). The author or inventor of more than 145 peer-reviewed scientific publications and patents, Simeonov has a truly diverse background, ranging from bioorganic chemistry and molecular biology to clinical diagnostic research and development. He received a Ph.D. in bioorganic chemistry from the University of Southern California and a B.A. in chemistry from Concordia College. Simeonov then trained as a postdoctoral fellow at the Scripps Research Institute under Richard Lerner and Kim Janda. Prior to joining NIH in November 2004, Simeonov was a senior scientist at Caliper Life Sciences, a leading developer of microfluidic technologies, where he was responsible for basic research on novel assay methodologies and development of microfluidic products for research and clinical diagnostics.
Throughout the whole of Europe, Dunn Labortechnik GmbH distributes since more than 35 years general laboratory equipment, consumables and immunoreagents. We are the principal distributor and service team for the liquid handling and imaging systems from Art Robbins Instruments in Europe.
The focus of this session will be on emerging biological targets covering the epigenetic target space, targets of the ubiquitin system and novel, innovative approaches targeting specific protein kinases.
Dr Louise Berg, Karolinska Institutet
The presentation will include a description of the experimental platforms used, immune mechanisms involved in the pathogenesis of the diseases we study, and results from the screening of 30-50 inhibitory compounds using these platforms. The majority of these compounds target epigenetic regulators and protein kinases. The discussion will focus on how we define compound effects and how we validate such findings. In addition, the relevance of setting up patient-derived assays early in the drug discovery process will be discussed, and how to run collaborations between the pharmaceutical industry and academic researchers, including access to clinical sample and expertise.
Place a charging station next to or in your booth, or at a key location in the exhibition to attract participants who are always looking for ways to charge their mobile devices.
Your branding and an invitation to visit your stand can be part of the design of the sought-after mobile charging stations.
The charging station consists of 4 secure lockers and will be available during the 3 days of the conference.
Directional-style 1 sqm floor stickers positioned in close proximity to your booth to enhance visibility and remind participants to stop by.
Reach attendees with your branding or message on strategic places. These are single-sided banners that attendees will travel past on a continual basis on their way to the exhibition hall or session rooms.
Reach attendees as they gather in the exhibition hall. Your company message will be on the banners above the short side of the hall.
Place your message on the extended wall just to the left of the Registration Area. Attendees will travel past this message to reach the exhibition hall. Furthermore, it is one of the first eyecatchers upon entrance.
Reach attendees as they gather in the hallway towards the conference. Your company message will be on the banners above the entrance. These are single sided banners that attendees will travel past on a continual basis.
Attendees use and walk past the escalator several times a day. Place your company’s artwork on the escalator at the entrance that takes attendees to and from the conference rooms. Attendees won’t be able to miss your message or branding.
Welcome attendees and be the exclusive sponsor of the Conference mobile app!
Please note that this option is limited to one company.
Help all attendees get connected at the conference as the official WiFi sponsor.
Please note that this option is limited to one company.
Lanyards provide highly visible recognition throughout the conference. Place your company logo prominently on the lanyards that are distributed to all conference participants who are required to wear them throughout the event. Lanyards will have to be produced in 1 colour and provided by the sponsor.
This option is limited to one company
Presented to each conference visitor upon registration, the official conference backpacks are used during and after the conference providing maximum marketing impact.
The communication package includes:
Seat drops are the ideal way to provide participants with information on your company’s latest innovations or information.
1-page advert in the conference pocket guide that will be provided to all conference attendees.
Your 1-page colour advert will provide you with significant exposure to all the participants (no cover/back cover).
The PDF of the program will also be made available on the Conference website ensuring a profound visibility to a wide audience.
Bag inserts are the ideal way to provide participants with information on your company’s latest innovations.
Please note that inserts can be flyers only.
At the end of the day, visitors and attendees will appreciate a refreshing drink during a reception in the exhibition hall. Networking is key, and you as the sponsor can benefit from the presence of this audience by a short presentation of your company and its activity.
Optional (provided by the sponsor):
The reception takes place on Wednesday, 27 June from 17:30 – 19:00. There are no sessions at the same time.
Be the only company to brand the walking dinner, a unique opportunity to welcome a wide audience of attendees with a speech in which you can present your company.
Optional (provided by the sponsor):
Standing banners (to be approved by SLAS and the venue based on security conditions).
SLAS is open to any other suggestion to improve your sponsor experience during the walking gala dinner.
Limited to 1 company.
Coffee breaks, scheduled during specific times in the exhibition and poster area, will represent an important time for participants to gather and engage in animated discussions between sessions.
The allocation of breaks will be done on a first-come-first-served basis.
Lunch breaks will represent an important time for participants to gather and engage in animated discussions.
An original tricycle as a food truck at the entrance is a particularly attractive eye-catcher. This tricycle would be branded with your logo and company name. Enjoy a coffee and a Brussels waffle before registering.
This service will be organized each morning (including 200 waffles and 200 coffees).
Benefit from the presence of a wide audience during a session to engage people to know more about your company. Create curiosity about your brand and products and invite them to your booth to engage with them on a personal level after your session.
Take advantage of organising your own user group meeting during the Conference, an ideal way to get your customers’ feedback on new products, developments etc.
The user group meeting is by invitation only, therefore, you have the right to invite your targeted audience.
Information about the session will be included in the pocket guide.
To view available slots go to slaseurope2018.org/sponsorship-availability
In order to support your goals, SLAS offers the opportunity to organize your own one-hour company workshop or training session in a branded private breakout room for up to 45 people seated.
To view the available slots go to slaseurope2018.org/sponsorship-availability
Size 2x2m. Located in the exhibition hall.
Shell scheme with a lockable door.
An excellent entry level for start-ups to get exposure, network and engage with all participants. It’s an ideal way to gather new leads or meet potential investors.
Booth 3×9 m
Make sure to be visible in our photo library by sponsoring the photo shoot and get your logo linked to the pictures of the event. Price for 1-day covering.
This session will cover the space from validated screening and identification of hits through to Candidate selection, and consider technologies and tools that are currently utilised or being investigated to improve the progression of quality molecules. This will include a focus on compound properties, pharmacological validation and target engagement at the site of action.
The focus of the session will be on achieving meaningful knowledge from big data. The speakers are experts in using large data sets from functional cell-based testing, image data as well as – omics to understand (health and) disease. We will discuss data reproducibility, how to turn images into quantitative data, (artificial intelligence-based methods) as well as integration of –omics data towards early drug discovery, clinical trials (and clinical practice).
The focus of the session is on the multiple approaches currently in development to address rare diseases, including gene and cell therapy, pharmacological chaperones to improve protein folding and stability and enzyme replacement therapy, among others.
This session is focused on the combined use of predictive model systems and multiparametric readouts in the iterative search for high-quality lead compounds. Particular attention is on protein tagging in primary cell types and comparisons of target engagement with downstream proximal and distal functional effects in high throughput formats. Case studies will describe combinations of approaches for a detailed understanding of mechanism of action.
The session will include the use of precise gene editing technologies (TALEN, CRIPR, etc) in combination with the use of primary cells, and other biological systems for drug discovery and other applications.
The combination of emerging knowledge in disease biology with time-tested and novel enabling technologies, best practices in medicinal chemistry and pharmacology, holds the promise to address the most urgent gap in pharmaceutical research: the discovery and validation of novel drug targets with the translational power to transform disease diagnosis and treatment. The speakers in this session will present case studies in different therapeutic areas to highlight how early discovery portfolios are changing to address the draught of tractable, safe and efficacious targets.
The session will cover topics such as the use of organoids, iPS derived models, etc, and how this is being used to discover new pharmacological targets and drugs with novel mechanism of action.
This session will focus on how understanding the molecular basis of the different mechanism involved in cellular ageing and degeneration can be used to discover drugs with new mechanisms of action.
The Networking Area is an ideal way to boost your visibility at the exhibition hall. Participants will be using this area during all breaks.
10 branded high tables & seats, carpet and 2 brochure racks.
Optional (provided by sponsor):
Two roll-up banners.
Sponsor the recording of one key presentation, that will then be available online for 12 months after the conference maximising the reach to the widest possible audience.
Videos will be available for free to all SLAS members and conference attendees.
Logo prominently displayed on the capture of session web page for 12 months
Your company recognised prominently on communications announcing the content capture.
50-word corporate profile on the conference website expanded to 150 words.
Optional (provided by the sponsor):
A 15-second promotion video or a logo could be added at the beginning of the video.
Organise a User Group Meeting during the conference. By invitation only (to be done by you).
Room with furniture.
Information about the session will be added to the pocket guide.
Wednesday 28 June, 8:00 – 10:00
Make sure to be visible in our photo library by sponsoring the photo shoot and get your logo linked to the pictures of the event.
Price for 1 day.
Attendees appreciate the simple availability of water. Place your eye-catching company designed message on 7 water stations in the exhibit hall and hallways.
1 eblast sent to the SLAS Europe database.
Limited to 2 companies.