Maximizing Efficiency in Discovery header


About This Conference:

In this genomic era of drug development, there has undoubtedly been a significant increase in novel drug targets and chemical compounds being investigated by developers. Yet, despite our continued success in unlocking the druggable genome, the ability to efficiently translate novel science to meet patients in need has declined, due to mounting reports of compounds displaying lack of efficacy or toxicity in early phases of clinical trials. With attrition rates climbing, developers are being challenged to respond by becoming more efficient during preclinical activities by identifying "right" targets and mechanisms of action; selecting "right" compounds without mechanism-based, compound-based or off-target toxicities, and utilizing disease-relevant models to validate and identify translatable biomarkers to enable POC earlier in development. These efforts are being recognized as viable options for novel targets to shift attrition to earlier, more cost effective stages, while improving transition through clinical trials.  



Thursday, October 9

11:30 am Registration


1:00 pm Plenary Keynote Program 
 

Chas BountraChas Bountra, Ph.D., Professor of Translational Medicine & Head, Structural Genomics Consortium, University of Oxford

Martin TolarMartin Tolar, M.D., Ph.D., Founder, President & CEO, Alzheon, Inc.

Andrew L. Hopkins, Andrew L. Hopkins, D.Phil, FRSC, FSB, Chair of Medicinal Informatics and SULSA Research Professor of Translational Biology, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee


2:45 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Chairperson’s Opening Remarks

Meir Glick, Ph.D., Head, In Silico Lead Discovery, Novartis Institutes for BioMedical Research, Inc.


HIGH-THROUGHPUT CHEMICAL DIVERSITY

3:55 FEATURED PRESENTATION: Industrializing Drug Discovery – Make More Compounds and Better Compounds and Make Them Faster

Russell C. Petter, Ph.D., Vice President, Chemistry, Celgene

I will discuss Celgene's approach to achieve two simultaneous goals – making more compounds and making better compounds. The former is achieved by several methods, but key among them are (1) incentivizing synthetic throughput, (2) cracking open the key bottleneck of synthetic productivity (chromatography), and (3) trying to focus design on sets of compounds rather than individual compounds. The latter requires (1) assessing the drug-likeness of compounds proposed for synthesis and (2) assaying for drug-likeness (e.g., in vitro and in vivo DMPK) preemptively rather than only after target-directed assays. My discussion will cover placing high-throughput medicinal chemistry (HTMC) on the critical path, using statistical concepts and methods in designing med chem experiments, automating chromatography to the point where it’s “frictionless”, making microsomes, solubility, Caco-2 permeability and the like into primary assays, taking on challenging high-sp3 molecules (including macrocycles) that increase the odds of good DMPK, and advancing sufficient chemical equity into early development such that chemistry is actually driving programs into clinical POC.


ADVANCES IN Physiologically relevant systems and PHENOTYPIC DISCOVERY

4:25 Toward Enabling Physiologically Relevant Assays: Taking Advantage of 3D/Complex Cell Systems for Drug Discovery

Christophe Antczak, Ph.D., Laboratory Head, CPC Integrated Lead Discovery, Novartis Institutes for BioMedical Research

In vitro organoid models are emerging that maintain aspects of in vivo tissue organization and function. Those complex cell systems, by recapitulating the multi-cellular 3D organization of tissues observed in vivo, may better mimic physiological conditions; in turn, more predictive assays may emerge by screening those complex cell systems. However, challenges exist in the path toward enabling high-throughput screening with such models, such as simplifying long and complex workflows, facilitating the handling of cells in suspension, and designing minimally invasive readouts. Overcoming such challenges might be the key to uncover the Holy Grail of drug discovery: to reduce the attrition rate of drug candidates in the clinic.

Evotec4:55 Success is Key in Innovation Efficiency

Craig Johnstone, Ph.D., Senior Vice President, Drug Discovery and Innovation Efficiency, Evotec

Creating success while others fail for lack of speed, quality or willingness to take risk is the task at hand in drug discovery. All projects encounter multiple technical problems, and so success must stem from solving or circumnavigating those problems in an effective manner. Finding the way forward in these circumstances requires experience, intellect, invention, seamless cooperation, slick execution and a passion for success.

5:25 Coffee Break in the Foyer

5:40 Regenerative Medicine Drug Discovery: Increasing Effectiveness in Drug Discovery Using Physiologically Relevant Human Cells and Biologically Annotated Compound Libraries

Alleyn Plowright, Ph.D., Senior Principal Scientist, Medicinal Chemistry, AstraZeneca

The use of physiologically relevant human cells, including primary cells from patients and human induced pluripotent stem cells, in compound phenotypic screening and toxicology testing, has the potential to transform drug discovery and lead to significantly improved outcomes in clinical development. Application of high content screening (e.g. multi-lineage differentiation), use of defined biologically active and annotated compound libraries combined with bioinformatic pathway analyses to phenotypic screens using these cells can maximize the knowledge gained and provide compound hits and targets relevant to modifying human disease. Challenges lay ahead including target deconvolution and the potential need to optimize chemistry against multiple targets. This presentation will describe advances in this area, including application in the field of identifying novel therapeutics for regeneration of cardiac tissue, and discuss the exciting opportunities as well as challenges that this approach will provide.

6:10 Tackling Metastasis through a Phenotypic Assay: Discovery of Compounds that Reduce the Perinucleolar Compartment

Samarjit Patnaik, Ph.D., Research Scientist, Probe Development Center, NCATS, NIH

The perinucleolar compartment (PNC) is highly prevalent in metastatic tumors, metastatically transformed cancer cell lines, and in cancer stem cells. Using a high content imaging assay we have discovered a chemical series that is able to reduce PNC prevalence in multiple cells lines without significant impact on cell viability. The lead compound shows in vitro anti-oncogenic properties including inhibition of migration and invasion. When tested in a pancreatic mestastasis model, derived from pancreatic cancer stem-like cells, that recapitulates human pancreatic cancer progression including distal metastasis and carcinomatosis as well as impaired drug perfusion at the primary tumor site, daily treatment at 5 mg/kg or 25 mg/kg for 5 weeks significantly reduced metastasis to the lung and liver with no signs of toxicity.

6:40 Close of Day

7:00 Dinner Short Courses*


*Separate registration required
 


Friday, October 10

7:30 am Registration

8:00 Interactive Breakfast Breakout Discussion Groups

Enjoy breakfast while joining a discussion group. These are moderated discussions with brainstorming and interactive problem solving, allowing conference participants from diverse backgrounds to exchange ideas, experiences, and develop future collaborations around a focused topic.

Addressing Bottlenecks in Data 

Meir Glick, Ph.D., Head, In Silico Lead Discovery, Novartis Institutes for BioMedical Research, Inc.

  • Live cell imaging: data storage (this is more challenging than NGS), image analysis approaches (e.g. how to link a morphological change to a target?) How to compare profiles of compounds across multiple imaging assays?
  • Linking compounds directly to complex phenotypes without knowing the target?
  • Pathway databases (KEGG, GeneGo) that we often use are too generic. With the increasing usage of cell engineering do we need to do a better job curating and leveraging these important data sources?

Target Deconvolution from Phenotypic/High-Content Screens 

Samarjit Patnaik, Ph.D., Research Scientist, Probe Development Center, NCATS, NIH

  • Molecule with tags for affinity chromatography: How to choose the right tag for your small molecule? Where and how to attach it? Linker length. Bifunctional tags. Tags with reporters or irreversible war heads. New techniques (fluorous, tosyl groups).
  • Gene arrays. Protein arrays. Expression Cloning methods. Biochemical Suppression.
  • Yeast and mammalian Hybrid systems
  • Does target identification matter that much?

 

ENSURING TARGET ENGAGEMENT

9:00 Chairperson’s Remarks

Alleyn Plowright, Ph.D., Senior Principal Scientist, Medicinal Chemistry, AstraZeneca

9:10 Improving Translation in Drug Discovery by Monitoring Target Engagement Using CETSA

Michael Dabrowski, Ph.D., Associate, Pär Nordlund Group, Research Division of Biophysics, Karolinska Institute; CEO, Pelago Biosciences AB

We have developed a novel generic method for evaluating drug binding to target proteins in cells, tissues and organs. The Cellular Thermal Shift Assay (CETSA™) is based on the physical phenomenon of ligand-induced thermal stabilization of target proteins. Using this technique, it is possible to quantify drug-target interactions completely label free. We have validated the translational utility of the method to monitor drug binding and mode of action of the native target in physiological relevant conditions in in vitro cell cultures and in vivo samples from mice and man for a set of important clinical targets. Data from numerous applications greatly facilitating the Drug Discovery Value Chain, including target identification and validation, lead generation/optimization, specificity and selectivity studies, drug transport and activation, treatment resistance development as well as efficacy, distribution and safety studies will be presented and discussed.

9:40 Positron Emission Tomography (PET): Enabling Earlier, More Confident Decisions in Drug Discovery and Development

Eric Hostetler, Ph.D., Lead, PET Tracer Group, Merck Research Laboratories

Over the last decade there has been an explosion of novel targets and the pace of drug discovery has never been faster. However, pharmaceutical industry productivity has been decreasing at a steady rate, spending more to discover fewer drugs. Given the probability of success, Phase II as the default clinical decision-making stage is not sustainable. Attrition can be shifted to earlier stages of drug development by better use of biomarkers. We will discuss PET tracer discovery and how PET can be integrated into Phase I trials to ensure target engagement, focus dose range, and maximize benefit to risk for clinical drug candidates.

10:10 Coffee Break in the Exhibit Hall with Poster Viewing


DEVELOPMENT OF HIGH-QUALITY CANDIDATES: IMPROVED DMPK CRITERIA, NOVEL DATA ANALYTICS AND EXPLOITING POLYPHARMACOLOGY

10:55 A Proposed DMPK Screening Paradigm for Efficient Discovery of Reversible and Irreversible Drugs

Mehran F. Moghaddam, Ph.D., Head, Drug Metabolism and Pharmacokinetics, Celgene

Discovery of high-quality drug development candidates in an efficient, timely, and cost effective manner remains to be a challenge for the biopharmaceutical industry. Resource and time constraints have forced discovery groups to seek compound advancement criteria that allow faster discovery of compounds with the most probability of clinical success and remove the low quality compounds in a speedy, efficient, and economical manner. In this presentation, our proposed screening paradigms for discovery of non-covalent and covalent drugs and their nuances will be discussed.

11:25 In silico Lead Finding through Holistic Understanding of Screening Data from Multiple Approaches

Meir Glick, Ph.D., Head, In Silico Lead Discovery, Novartis Institutes for BioMedical Research, Inc.

The changing drug discovery environment presents a richer, more complicated and novel data landscape. How can state-of-the-art data analytics increase the probability of a lead compound to be disease relevant? We will discuss how in silico approaches actively shape the lead discovery process: informing on relevant assays, compounds subset design to probe the biology, visualization of complex biological data, models elucidating target / MOA hypothesis and design of chemical matter.

11:55 Novel Inter-Omics Approaches for Big Data Analysis and Drug Discovery

Shuxing Zhang, Ph.D., Head, Integrated Molecular Discovery Laboratory; Director, Molecular Modeling/Structural Biology Core; Assistant Professor, Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center

The large scale data available to date can help us understand cancer biology and accelerate development of novel agents for targeted therapies. We recently embarked on the implementation of novel inter-omics approaches by integrating concepts and technologies in cheminformatics, bioinformatics, and systems biology. These tools have significantly sped up our analysis of the big chemogenomics data and guided our translational cancer research. In particular, we have built an integrated platform to explore drug polypharmacology which was successfully applied to development of novel potent cancer therapeutics by targeting critical protein ubiquitination and translocation pathways.

Shamrock Structures12:25 pm Accelerate Your Drug Discovery R&D with Protein Crystallography, Medicinal Chemistry and Cell Biology Research Services from Shamrock Structures

Michael T. Flavin, Ph.D., CEO, Shamrock Structures, LLC

Shamrock Structures can enable your team to more rapidly discover potent and selective new drug lead compounds. Our scientists can help characterize your protein target with X-ray crystallography, synthesize small molecule analogs and fragments for target binding and screen your compounds against oncology targets to determine potency and selectivity.

12:40 pm Selected Poster Presentation: Advantage of TPIMS Small Molecule Libraries for Phenotypic Screening 

Marc Giulianotti, Director, Chemistry Operations, Torrey Pines Institute for Molecular Studies

The Torrey Pines Institute (TPI) lead generation library consists of more than 30 million compounds designed around 65 molecular scaffolds systematically arranged in positional scanning and scaffold ranking formats. These formats allow for the analysis of millions of compounds through the use of just hundreds to thousands of samples. This is highly advantageous as it allows one the opportunity to screen the entire collection, circumventing the need to use focused or target libraries in order to reduce the number of samples to screen. In fact the reduction in sample size has allowed for the successful use of the library directly in phenotypic in vivo studies. The diversity of the TPI lead generation library has been characterized and described quantitatively by means of molecular scaffolds, molecular properties, and structural fingerprints. The library collection provides unique lead compounds suitable for optimization for advancement to preclinical and, ultimately, clinical studies. Recently the superior effectiveness of the TPI lead generation library in comparison to the use of the Prestwick Chemical Library (PCL), MLSMR, and a computational screen for the identification of formyl-peptide receptor ligands was reported. Because of the nature of the TPI library collection, a large quantity of SAR is generated with each screen and the resulting hit series contain sets of close structural analogs with multiple diversity points ideally suited for medicinal chemistry optimization. Additionally the synthetic route to every compound in the entire TPI library has already been developed.

12:55 Session Break

1:05 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:45 Session Break


CASE STUDIES IN EPIGENETICS: EXPANDING CHEMICAL SPACE INTO PPI AND ALLOSTERY

1:55 Chairperson’s Remarks

Eugene Chekler, Ph.D., Senior Principal Scientist, Medicinal Chemistry, Pfizer

2:00 Targeting the MLL1-WDR5 Protein-Protein Interaction as a Novel Therapeutic Strategy for Acute Leukemia Harboring MLL1 Fusion Protein

Shaomeng Wang, Ph.D., Director, Center for Discovery of New Medicines; Warner-Lambert/Parke-Davis Professor, Medicine, Pharmacology and Medicinal Chemistry, University of Michigan Comprehensive Cancer Center

I will present our structure-based design of highly potent and specific small-molecule inhibitors of the MLL1-WDR5 protein-protein interaction as a new therapeutic strategy for the treatment of acute leukemia harboring MLL1 fusion protein. Their mode of action and therapeutic potential will be discussed.

2:30 Targeting Arginine Methyltransferases

Masoud Vedadi, Ph.D., Principal Investigator, Molecular Biophysics, Structural Genomics Consortium; Assistant Professor, Department of Pharmacology and Toxicology, University of Toronto

Epigenetic regulation of gene expression through histone methylation has been implicated in a variety of diseases. Protein arginine methyltransferases (PRMTs) is an emerging class of therapeutic targets. We previously reported the first allosteric inhibitor of PRMT3 with an IC50 value of 2.5 µM, and a significantly more potent next-generation inhibitor with an IC50 value of 230 nM. Here we will report on further optimization of this series of inhibitors (less than 100 nM), discuss their target engagement in cells, and possible allosteric inhibition of other PRMTs. We also report on our progress in targeting active sites of all PRMTs.

3:00 Refreshment Break in the Exhibit Hall with Poster Viewing


MODERN DRUG DISCOVERY: A RIGOROUS APPROACH TO TARGET VALIDATION

3:30 Target Validation Using Chemical Probes in Medicinal Chemistry

Eugene Chekler, Ph.D., Senior Principal Scientist, Medicinal Chemistry, Pfizer

Fully profiled chemical probes are essential to support the unbiased interpretation of biological experiments necessary for rigorous preclinical target validation. We believe that by developing a chemical probe tool kit, chemical biology can have a more central role in identifying targets of potential relevance to disease, avoiding many of the biases that complicate target validation. A development of CREB Binding Protein (CREBBP) selective chemical probe to elucidate biology associated with this bromodomain epigenetic target is presented. Chemical probe optimization is a strategic balance between physiochemical properties and chemistry, to identify high affinity binders that are functionally active and selective, with good permeability properties. The selectivity of the chemical probe against other bromodomain family members was investigated using biochemical and biophysical assays. To address the selectivity issue with BRD4, X-ray crystal structures of the probe candidates bound to CREBBP and BRD4 were used to guide the design. The chemical probes were useful in studies aimed at validating CREBBP as a therapeutic target and for establishing its biological role.

4:00 Development of Highly Potent and Selective Reversible Covalent BTK Inhibitors

Erik Verner, Ph.D., Director, Chemistry, Principia Biopharma

4:30 Evaluation of Cancer Dependence and Druggability of PRP4 Kinase Using Cellular, Biochemical and Proteomic Approaches

Qiang Gao, Ph.D., Senior Investigator, Oncology, Sanofi

In this presentation, the requirement of enzymatic activity of PRP4 in regulating cancer cell growth is reported. An array of novel proteomics approaches for its substrates identification is proposed and transferable to exploring the kinase substrates for other kinases. The work presented is an unprecedented effort in big pharma for identification of substrates for novel kinase, which paves the way for exploring the substrates as surrogate pharmacodynamics biomarkers in a biologically-relevant setting. The result presented will shed light on the design of HTS assay for screening inhibitors for PRP4. As PAK4 was the first native substrate identified for PRP4 in cell, the biochemical assay for HTS screening designed based on this result would facilitate the translation of in vitro potency to in vivo efficacy. To facilitate the understanding of the PRP4 kinase domain in more detail for the research community, the X-ray crystal structures will be reported, including the apo, ADP, AMPPNP-, and compound A-bound kinase domain of PRP4. To our knowledge, this is the first structural information ever reported. Specifically, a robust and straightforward platform for purification and crystallization of human kinase domain amenable to both co-crystallization and soaking of apo crystals will be discussed. This system is critical for efficient structural biology support during the drug discovery process since the ability to produce a high number of structures in complexes with different ligands in a rapid fashion is essential for driving the optimization of selected chemical series. Finally, I will present a tool compound A, for which reported to be co-crystallized with PRP4, could be a good starting point to incorporate these hypotheses into future medicinal chemistry efforts. Using the aforementioned information, along with virtual docking, one may be able to generate a potent and selective PRP4 inhibitor for future biological studies.

5:00 Close of Conference



Suggested Event Package:

October 7 Short Course: Approaches for Biologically-Relevant Chemical Diversity 

October 7 Short Course: Advances in Metagenomic Drug Discovery for New Anti-Infective Agents 

October 8-9: Big Data Analytics and Solutions Conference 

October 9-10: Maximizing Efficiency in Discovery Conference 


*Separate registration is required


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PREMIER SPONSOR 

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SPONSORSHIPS & EXHIBITS 

The exhibit hall was sold out in 2013, so please contact us early to reserve your place. To customize your sponsorship or exhibit package for 2014, contact:

Jon Stroup
Business Development Manager
781-972-5483
jstroup@healthtech.com 

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