Register 3 for the price of 2 with the coupon code RCDVB!

12:00

Registration

1:00

Current Perspectives in Fragment-based Drug Discovery

Roderick E. Hubbard
Senior Fellow, Professor
Vernalis (R&D) Ltd, University of York

The past ten years has seen tremendous developments in the experimental methods of fragment-based discovery, with many compounds now in clinical trials and the first compound now on the market. The central feature is that the drug discovery process begins with identification of small (<250 MW), weakly binding (affinity of 100s of µM) compounds which are then optimised to drug candidates by structure-guided design. The advantages are that a small library can sample a potentially large chemical diversity to generate novel lead compounds and that hits can be identified for new classes of target where existing compound collections fail.

I will briefly review the current status of the methods and their application and survey some of the current issues. These include: deciding which fragments to progress; introducing more 3d fragments; and how to work with non-conventional targets, such as protein-protein interactions.

1:45

Building the Scientific Basis for NORD's Advocacy Agenda: 2013 and Onward

Michael Scott
Board of Directors
NORD

It has been 30 years since NORD was founded on May 4, 1983 to be the primary advocate and independent champion for the needs of rare disease patients and families across America -- exactly 4 months after Ronald Reagan signed the original Orphan Drug Act into law. A great deal has been accomplished in the ensuing 30 years, and over the past 18 months NORD has been looking hard at itself and the services we provide to the various communities we now engage with. New bioscientific advances are radically changing our ability to more rapidly and accurately diagnose and potentially treat the 30+ million Americans living with any one of about 6,500 rare disorders. This presentation will lay out NORD’s current and evolving perspective of its future mission and vision, with a specific emphasis of how NORD is proposing to increase its efforts to meet the underlying scientific and clinical needs of rare disease patients, their families, the physicians skilled in diagnosis and treatment of these disorders, and the varied members of the basic and translational science communities who are increasingly engaged in the hunt for better diagnostic technologies and therapeutic opportunities.

 2:30

How New Medicines Are Discovered: Strategies to Increase Success

David C. Swinney
Chief Executive Officer
Institute for Rare and Neglected Diseases Drug Discovery

Successful drug discovery is facilitated by a good starting point and strategy. Prior to the molecular and HTS revolution in medical research, starting points were empirical, phenotypic assays using small focused chemical libraries. Starting points after the molecular revolution combined screening at specific gene targets and large, diverse compound libraries. This approach, while having some success most notably in cancer, has yet to transform the industry. In fact the majority of first-in-class, small molecules NMEs approved by the US FDA between 1999 and 2008 were discovered using the phenotypic strategy. In this talk I will discuss the challenges and potential opportunities to assimilate the strengths of both these past strategies to increase the chance for success..

3:15

Afternoon Networking & Poster Session

4:30

End of Day 1

7:00

Registration & Continental Breakfast

7:55

Welcoming Remarks

FEATURED PRESENTATION

8:00

FBDD of Orally Active, Brain Penetrant BACE Inhibitors

Frank Brown
Associate Vice President
Merck

The FBDD approach to orally active, brain penetrating BACE inhibitors will be discussed. The integrated use of BioNMR and X-ray crystallography to design and optimize BACE inhibitors is the main theme of the presentation.

8:25

Identification of JNJ 31020028, a Selective Brain Penetrant and Small Molecule Antagonist of the NPY Y2 Receptor

Devin Swanson, Senior Associate Scientist, Johnson & Johnson

Neuropeptide Y (NPY) is the most abundant peptide in the brain and is widely distributed throughout the central and peripheral nervous system. Its localization has suggested a role in a variety of physiological processes including food intake, anxiety, hormone release, and memory. The NPY Y2 receptor is one of five identified G-protein coupled receptors that bare its name (Y1, Y2, Y4, Y5, y6). Unlike other NPY receptors, Y2 is a pre- and postsynaptic receptor that regulates the synthesis and release of NPY. Thus antagonism of the receptor is thought to elevate levels of NPY in the synapse to the benefit of CNS disorders. A series of small molecules based on a chemotype identified from our initial high throughput screen were synthesized and tested at the human NPY Y2 receptor. One member of this series, JNJ 31020028, was found to be a high affinity, selective, receptor antagonist that penetrates the brain after s.c. administration.

8:50

Discovery of a Novel Tricyclic Inhibitor of Janus Kinase 2 (JAK2) for the Ttreatment of Myeloproliferative Disorders

Michelle Machacek, Senior Research Chemist, Merck

The JAK-STAT pathway is a key signaling pathway for both hematopoiesis and immune responses. A single activating mutation in the JAK2 pseudokinase domain leads to cytokine-independent proliferation and survival of hematopoietic cells and has been found in a high proportion of patients with myeloproliferative disorders (MPDs) such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis. The clear link between deregulation of JAK2 and disease has prompted the development of small molecule inhibitors for MPDs. This talk will describe efforts culminating in the discovery of a novel inhibitor of JAK2, including lead hopping efforts to identify an aminocarboline scaffold and optimization of potency and physical properties to afford compounds with favorable selectivity and pharmacokinetic profiles.

9:15

Rising Targets in the Protein Misfolding Space

Eddine Saiah, Director of Medicinal Chemistry, Pfizer

There is an increased interest in the pharmaceutical research industry in tackling protein misfolding. Potential therapeutic indications include neurodegeneration, cancer, diabetes, cystic fibrosis and other genetic diseases. Targets in the protein misfolding space are challenging since the target molecules are not necessarily agonists, antagonists or active site binders. Instead, the research focus is on small molecules that can either stabilize the protein in a native or near-native conformation and/or prevent protein aggregation and misfolding. In the present talk, we will present an overview on the recent advances in this exciting area as well as specific targets of current interest based on recently published literature.

9:40

Ligandable Proteins Without Ligands: A Gap Analysis of Global Pharmacology

Jeremy Jenkins, Senior Scientist, Novartis

We present an analysis of the gaps between what human proteins have been targeted by small-molecules versus the complement of human proteins that are predicted to be ligandable. To assess ligandability, we apply a structural genomics approach to identify Interpro and PFAM domains that are found bound to lead-like chemicals in X-ray co-crystal structure complexes from RCSB Protein Data Bank. Theoretically ligandable proteins are those that contain these domains. Next, we integrate large-scale databases of compound-target bioactivities with semantically standardized target nomenclature to understand the scope of human proteins currently ‘covered’ by chemical biology. Finally, we merge the two approaches in order to understand what protein targets are accessible to small-molecule modulators but have yet to be targeted by global pharmacology, with an eye on up-and-coming target families.

Benefits:
- Understand how integrating pharmacology data yields emergent discoveries
- Get a high-level view on what drug targets are ripe for lead finding
- Get a first look at a reproducible approach to assessing druggability
- See an industry-leading data warehouse applied to large-scale drug discovery questions

10:05

Morning Networking & Coffee Break

10:30

Using Small Molecules to Engineer and Explore Human Immune Responses

David Spiegel, Associate Professor of Chemistry, Yale University

Antibody-based therapeutics have become critical instruments in treating diseases ranging from rheumatoid arthritis to cancer in recent years. However, antibodies and other therapeutic proteins are limited in therapeutic applications by their chemical structures: because they are peptide-based, they require intravenous administration, are often highly immunogenic or allergenic, and treatment regimens are often very costly.
This talk describe recent research efforts in our laboratories toward the design, chemical synthesis, and biological characterization of small molecule antibody recruiting therapeutics against prostate cancer, Staphylococcus aureus, and the human immunodeficiency virus (HIV). These are bifunctional small molecules designed to redirect antibodies already present in the human bloodstream to the surfaces of pathogenic cells, such as cancer cells, bacteria, and virus particles. The ternary complex formed between these agents, endogenous antibodies, and target cells will lead to immune-mediated pathogen destruction. In theory, this strategy would exploit many of the advantages of biologics, while circumventing the disadvantages, by capitalizing on the chemical properties of small molecules (e.g., high oral bioavailability, facile synthesis, and low cost).

It is our hope that this small molecule-based strategy will serve as starting point toward entirely novel scientific insights and therapeutic approaches relevant to a wide range of disease states.

10:55

Sirtuin Inhibitors as Anticancer Agents

Hening Lin, Associate Professor, Chemistry and Chemical Biology, Cornell University

Sirtuins are a class of enzymes with nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacylase activities. They have been found to be involved in a number of important biological processes, including the regulation of metabolism, genome stability, and life span. Small molecules that can regulate sirtuin activity showed promise in treating several human diseases, including cancer. It has been reported that sirtuin inhibitors have anti-cancer effect. However, among the seven human sirtuins, inhibiting which one produces the desired anti-cancer effect is not clear. This is partly due to the lack of specificity of the reported sirtuin inhibitors. Based on our enzymology studies with different human sirtuins, we have developed inhibitors that are specific for some of the sirtuins. In particular, we have a compounds with 50 nM IC50 value and is >1000 time selective toward Sirt2. This is the best Sirt2 inhibitor to our knowledge. This compound can inhibit the growth of many different cancer cell lines and can also inhibit tumor growth in a xenograft mouse model of triple negative breast cancer. The significance of our study is several fold. First, it establishes Sirt2 as a promising cancer target. Second, it provide a new and logic way to come out with inhibitors that are selective for one particular sirtuin. And finally, this method may be broad useful for the design of specific inhibitors for other type of enzymes, such as zinc-dependent HDACs.

11:20

Integrating Design, Analysis and Visualization into the Drug Discovery Workflow

W. Patrick Walters, Principal Research Fellow, Vertex Pharmaceuticals

Drug discovery is a complex process that involves the simultaneous optimization of multiple parameters. In order to be effective, a discovery team must be able to analyze data, identify trends, and decide on a direction for compound optimization. This analysis typically requires the synthesis of not only internal data, but also information culled from external sources such as patents and papers. Many informatics systems provide the ability to query internal data, but few offer the capability to integrate design tools with a combined analysis of internal and external data. Rather than simply combining all of the data into a single data warehouse, we have used facilities such as application programming interfaces (APIs) to create links to a wide array of relevant external sources. This presentation will use a few case studies to present some of our recent work to create a unified informatics infrastructure that allows facile access to internal data as well as a variety of literature sources.

• Seamless integration of in-house and literature information
• Streamline searches that would otherwise be labor intensive
• Provide a more thorough picture of SAR trends
• Gain insights into SAR through novel analysis and visualization

11:45

Finding and Applying Rules for Successful Drug Discovery

Matthew Segall, Chief Executive Officer, Optibrium

A high quality drug must exhibit a balance of many properties, including potency, ADME and safety. These are often expressed as property ‘rules’ that a compound must meet in order to progress. Applying these rules effectively in drug discovery is challenging due to the complex, often conflicting property requirements they reflect, combined with uncertain data because of experimental variability or predictive error. We will discuss how methods known as multi-parameter optimization (MPO) are currently being applied to quickly target compounds with the best chance of success, while avoiding missed opportunities.

But how do we know what rules to use to select good compounds? The property criteria depend on the objectives of the project, such as therapeutic area and route of administration and are typically determined by the project team, based on their opinions and experience. We will describe how new methods, known as rule induction (RI), can guide this process to identify multi-parameter rules that distinguish successful compounds for a chosen objective. The resulting rules are interpretable and modifiable, allowing experts to understand and adjust them based on their knowledge of the underlying biology and chemistry. Furthermore, the importance of each criterion can be identified, allowing the most important data to be prioritized to make effective compound prioritization decisions.

Benefits:
• Apply MPO to target high quality compounds with a balance of properties
• Consider uncertainty to avoid missed opportunities
• Objectively tailor compound selection rules to project objectives
• Prioritize the most important data to support compound selection decisions

12:10

Lunch On Your Own

1:45

New In Silico Strategies for “Hit” Identification and Optimization

Istvan Enyedy, Senior Scientist, Biogen-Idec

The Pharmaceutical Industry is now interested in modulating targets that are challenging from the drug design point of view. Thus the development of new in silico approaches and improvements in current technology are necessary for the design of compounds that modulate these targets. The use of information from known protein-ligand cocrystal structures for generating new starting points or for modifying/optimizing existing “hits” using in silico fragment-based strategies. Examples will be shown from using MED-SUMO and ATLAS in combination with docking software to generate new chemotypes. In addition challenges in selecting active compounds through docking and scoring will be presented.

Benefits:
• Using “hot-spot” prediction can help us focus our “hit” finding and optimization efforts
• MED-SUMO is a useful tool for mining experimental data to identify functional groups that are known to bind to protein features of interest
• The use of constraints can help us quickly identify fragments binding in the regions of interest in a binding site
• Hybridization tools can be used for building new compounds from the fragments identified

2:10

Exploiting Solvent Effects in Drug Design and Optimization

Chris Williams, Principal Scientist, Chemical Computing Group

When a ligand binds a protein, the structured solvent molecules in the binding pocket and around the unbound ligand become displaced or rearranged. These molecular reorganizations, in terms of desolvation, have a large impact on binding free energy, influence ligand design requirements and can introduce elements of ambiguity in traditional SAR analysis. Typically, computing the energetics of these reorganizations requires lengthy and expensive simulations. This talk presents an efficient method (3D-RISM) which computes, in the order of minutes, the thermodynamic effects of solvent reorganization without explicit simulations. The method can help locate regions of organized solvent and their corresponding free energies. Application of the method to ligand optimization is demonstrated using case studies which highlight the unique insights that can be gained from this type of analysis.

2:35

3D Searching in Very Large Virtual Combinatorial Compound Spaces

Ingo Mügge, Senior Research Fellow, Boehringer-Ingelheim

Virtually screening huge virtual combinatorial library spaces with the aim of synthesizing target specific libraries for lead identification has been pursued at Boehringer Ingelheim for some time (J. Chem. Inf. Model.2009, 49, 270?279; J. Med. Chem. 2012, 55, 11031). Here we present PharmShapeCC - a virtual screening approach that performs multi-conformational 3D pharmacophore and shape searches against more than 10 trillion compounds from tens of thousands of virtual combinatorial libraries. A PharmShapeCC query is created from a 3D pharmacophore model mapped onto one or more aligned template ligands. A composite inclusion shape component to the query is generated from the aligned ligands. Alternatively, inclusion shapes can be derived from protein structures. To prune the search space, PharmShapeCC makes use of the combinatorial nature of the compound deck as well as the hypothesis that active library compounds are likely to bind in similar binding orientations. PharmShapeCC search results will be compared to those obtained from searching exhaustively enumerated compound spaces with the same query and algorithm. Examples of successful identification of novel chemical space will be given.

3:00

Afternoon Networking & Coffee Break

3:30

Computational Structure Activity Relationship Approaches to Help in Hit to Lead Optimization

Jascha Blobel, Product Manager, Intelligent Pharma

Applying computational methods from early on in a Hit optimization process help the medicinal chemist in the design and decision making process. We show how general rules about the preferential molecular properties can be determined by using both statistical and also structure based approaches at the early stages of the Hit optimization process. This allows for a directed design of better Hits by the medicinal chemists. Still, the SAR rules require one to consider huge numbers of molecules. The selection of the most appropriate ones for synthesis and experimental testing may be achieved by computational models, which predict the activity and other favorable characteristics of the compounds. Therefore, the Hit optimization process may be accelerated by combining forces between a medicinal chemist and computational approaches designed by the modeler.

• Computational methods for Hit optimization
• Statistical and structure based approaches to determine molecular properties
• Molecules design using SAR
• Anti-infective Hit to Lead optimization

3:55

Computational Tools Supporting Fragment-Based Drug Design

Sandor Vajda, Professor, Biomedical Engineering, Boston University

Fragment based drug design (FBDD) starts with finding fragment-sized compounds that are highly ligand efficient and can serve as a core moiety for developing high affinity leads. Although the core-bound structure of a protein facilitates the construction of leads, effective design is far from straightforward. We show that protein mapping, a computational method developed to find binding hot spots, provides information that complements the fragment screening results and can drive the evolution of core fragments into larger leads with a minimal loss or, in some cases, even a gain in ligand efficiency (Brenke R et al., Bioinformatics, 25:621, 2009; Hall DR et al., J Am. Chem. Soc. 133:20668, 2011; Hall DR et al., J. Chem. Inf. Model. 52:199, 2012). In addition to providing information on druggability and on the selection of ligands, mapping also helps to improve docking results, both by indicating the appropriate location and size of the docking box and by ranking the docked poses (Kozakov D et al., PNAS 108:13528, 2011). The mapping algorithm has been implemented as the FTMap server (http://ftmap.bu.edu/), which enables testing our results and extending the analysis to other systems.

Some lessons to be learned:

• finding a tool for assessing druggability
• high accuracy identification of binding sites
• learning a web-based server for hit-to-lead design
• additional information for improving ligand docking results

FEATURED PRESENTATION

4:20

Structure Based Drug Design and Molecular Complexity: The Discovery of Highly Selective Inhibitors of mTor

Simon Bailey
Senior Director
Worldwide Medicinal Chemistry Oncology
Pfizer
 
 

The presentation will describe how X-ray co-crystal structures were used to design highly selective inhibitors of the protein kinase mTor with good drug-like properties. A key strategy was to incorporate elements of structural complexity to drive selectivity

4:45

Merging Covalent and Allosteric Opportunities: A Custom Strategy for Modulation of a Daunting Protein::Protein Interaction

Ellen Laird, Research Fellow, Computational Chemistry, Array BioPharma

The seven in absentia homolog (SIAH) proteins are E3 ubiquitin-protein ligases whose complexes mediate proteasomal degradation of target proteins. Recent studies in mouse models have shown that SIAH inhibition impairs tumor growth and metastasis, and these proteins have become attractive therapeutic targets in various cancers. Reported inhibitors of SIAH complexes have been limited to large peptides, suggesting scant opportunity for small molecule intervention. We have devised a novel strategy that combines covalent fragment screening, exploitation of an allosteric site, and structure-based design to develop potent compounds for the disruption of protein::protein interactions of SIAH1 and its substrates. The rationale for the strategy, development of requisite technologies, and the evolution of initial fragment screening hits to promising ligands will be discussed. The results of this study have validated the platform as generally applicable to challenging problems in drug discovery.

Oral Presentation from Exemplary Submitted Abstract

 5:10

A Strategy for Inhibiting Flavin-dependent Thymidylate Synthase

Irimpan Mathews, Staff Scientist, Stanford University

Thymidylate synthesis is the terminal step in the sole de novo synthetic pathway to deoxythymidine monophosphate (dTMP), a nucleotide essential for the synthesis of DNA. Thymidylate synthase (TS) catalyzes this crucial reaction. TS inhibition stops DNA production, arresting the cell cycle and eventually leading to "thymineless" cell death. Flavin-dependent Thymidylate synthase (FDTS) are encoded by the thy1/thyX gene and are structurally and mechanistically different from classical TS encoded by thyA and thyB genes. Classical TS use N5,N10-methylene-5,6,7,8-tetrahydrofolate (CH2H4folate) to reductively methylate 2’-deoxyuridine-5’-monophosphate (dUMP) producing dTMP. In contrast to classical TS reaction where the cofactor CH2H4folate provides both the H- and methylene group, in the FDTS reaction the H- is provided by the FADH2 and CH2H4folate is used only as a source for the methylene moiety. FDTSs are essential for cell survival of many pathogenic organisms (Treponema pallidum (syphilis), Bacillus anthracis (anthrax), Mycobacterium tuberculosis (tuberculosis), Mycobacterium leprae (leprosy), Borrelia burgdorferi (Lyme disease), Helicobacter pilori (gastric ulcer), Clostridium botulinum (botulism), Rickettsia prowazekii (epidemic typhus), and Chlamydia pneumoniae (pneumonia) are FDTS family members). FDTSs provide a unique alternative for the development of antimicrobials capable of simultaneously targeting a wide range of organisms. The absence of homology between FDTS and classical thymidylate synthase offers the possibility of developing inhibitors with low cross-reactivity with the human enzyme. We will describe the recently determined structures of the complexes of FDTS with methylenetetrahydrofolate and present a strategy for inhibiting this important class of enzymes.

 5:25

Evening Networking Reception

FEATURED PRESENTATION

 8:00

Consideration of the Molecular Mechanism of Action in Drug Design

David C. Swinney
Chief Executive Officer
Institute for Rare and Neglected Diseases Drug Discovery

One approach to drug design is improvement of reversible equilibrium binding affinity to a target. However, in many cases this approach does not consider other molecular mechanisms of action (MMOA). MMOAs that include the dynamic molecular interactions involved in conformational changes and binding kinetics can help translate the information from binding to a selective pharmacological response. An optimal MMOA increases the therapeutic index and consequently, a medicine’s usefulness. The challenge to a priori predict an effective MMOA was proposed to contribute to the success of phenotypic assays for first in class medicines and also is responsible for the requirement of empirical animal assays to derisk toxicity. Designing exclusively for affinity may miss key dynamic conformational and/or kinetic features required for an optimal therapeutic index. New approaches are needed in rational drug design that will identify candidates with an optimal MMOA.

8:25

Implementing Quantitative System Pharmacology in Drug Discovery and Development

Albert Gough, Research Associate Professor, University of Pittsburgh

We are implementing quantitative systems pharmacology (QSP) as a novel approach to drug discovery and development when combined with phenotypic methods using High Content Analysis (HCA). QSP is an approach to translational medicine that combines computational and experimental methods to provide an integrated “systems-level” approach to define the mechanism(s) of action of existing and new therapeutics. The integration of the best computational and experimental methods can create the knowledge needed to understand and modulate the complex cellular networks responsible for pathophysiology and toxicities. We are implementing QSP for understanding the heterogeneity of response within tumors and then developing optimal therapeutics to address this biological complexity. In addition, QSP is being applied to the development and implementation of a 3D, human biomimetic liver acinus model to be used as an early safety assessment platform to optimize the development of lead compounds.

• Increasing innovation in drug discovery and development
• Collaborations to advance drug discovery and development
• Implementation of human, cell –engineered models for discovery and development

8:50

Catalyzing Innovation at NCATS with Novel Public Private Partnerships

John McKew, Chief, Therapeutics Development Branch, Center for Translational Therapeutics, NIH

The National Center for Advancing Translational Science (NCATS) is a newly formed center within the National Institutes of Health. It was created by merging existing programs and several new initiatives into a new center. This new center now has two main divisions: the Division of Preclinical Innovation and the Division of Clinical Innovation. The Division of Preclinical Innovation encompasses the former NIH Center for Translational Therapeutics and provides a unique range of programs addressing many aspects of therapeutics development. The programs include the NIH Center for Chemical Genomics (NCGC) which is one of the Molecular Libraries screening centers; the Tox 21 programs; a multiagency collective in vitro toxicology screening program, Therapeutics for Rare and Neglected diseases program; a collaborative drug discovery and development program focused on preclinical to early clinical development of candidate therapeutics for rare and neglected tropical diseases, and Bridging Interventional Development Gaps (the former NIH-RAID program); a collaborative late preclinical development resource program. The division of clinical innovation is currently comprised of the clinical translational science awards. This talk will give an overview of the new center and highlight the translational research programs contained within.

Benefits:
1. Better understanding of the role the NIH and NCATS play in developing novel public private partnerships for therapeutic development
2. Understanding of the existing and newly developed preclinical development initiatives NCATS has announced along with their solicitation timelines.
3. Examples of successful collaborative projects from the Therapeutics for Rare and Neglected Diseases (TRND) and Bridging Interventional Development Gaps (BrIDGs) program portfolios.

9:15

Discovery of a Novel Covalent EGFR Mutant-Selective Inhibitor That is Wild-type Sparing

Robert Tjin, Senior Scientist, Celgene

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib. Unfortunately, most patients relapse due to the emergence and/or acquisition of secondary mutations or amplification of potential escape pathways. A T790M mutation in EGFR is detected in approximately 50% of patients with drug-resistant tumors, which renders erlotinib and gefitinib ineffective. Although irreversible inhibitors in current clinical studies, such as PF299804, BIBW2992 and HKI-272 demonstrate anti- EgfrT790M activity in vitro, they have higher affinity for wild-type (WT) EGFR, resulting in dose-limiting toxicity such as diarrhea and skin rash. We have developed a novel covalent irreversible inhibitor that selectively and potently inhibits both EGFRT790M and the initial activating EGFR mutations but, importantly, is WT-sparing. Such a drug has the potential to effectively treat first- and second-line NSCLC patients with EGFR mutations without causing the dose limiting toxicities associated with approved EGFR kinase inhibitors or those in clinical development. Further, covalent inhibitors provide many advantages including improvements in potency, selectivity, prolonged duration of action and translational biomarker opportunities.

9:40

New Strategies Employed for the Discovery and Optimization of Protein Kinase Inhibitors

Mark Ashwell, Vice President, Chemistry, ArQule

The presentation will describe strategies utilized to discover and optimize protein kinase inhibitors of c-Met, FGFR, AKT and others. These case-studies will illustrate the potential for utilizing hydrophobic residues within the ATP-binding cleft of inactive and auto-inhibited kinases for inhibitor identification and optimization. Characterization of the molecular interactions with these inhibitors and their target kinase will be described using biophysical, biochemical and cell based assays together with X-ray crystallographic and mutational studies.

Benefits:
Success in structure based drug discovery
Novel modes of kinase inhibition
Opportunities for increasing kinase selectivity
Information rich cross disciplinary approach to drug discovery and optimization

10:05

Morning Networking & Coffee Break

10:45

New Horizons in Hit & Target Identification

John Mathias, Senior Director, Head of Medicinal Chemistry, Inflammation & Remodeling, Pfizer

HTS is often much maligned & sited to exemplify one of the reasons Pharma productivity has fallen. Data from the Pfizer experience supports the contrary view that HTS has been a significant success story. This talk will provide specific examples of the many positive success stories that Hit ID by HTS has provided across that have profoundly shaped the current Pfizer Clinical & preclinical portfolio.

Key area for focus will be:
• Sharing the features that underlie successful HitID campaigns
• Assessing success across the expanding range of target types in our portfolio
• Evolving approaches to compound file & subset screening
• Combining Fragment Screening & Biophysics with HTS
• Use of Chemogenomic Libraries & Pre-Competitive Screening Collaborations to identify novel probes & targets

11:10

Development of In Silico Hypothesis for Target and Pathway Modulation Based on a Comprehensive Analysis of Cellular, Biophysical and Pathway Data

Meir Glick, Head, Lead Discovery Informatics, Novartis

The role of in silico screening in lead discovery is to improve the overall quality and number of leads by the development of an on-going hypothesis throughout the screening life-cycle. We have found that applying state-of-the-art in silico techniques before, after and importantly in parallel with HTS has resulted in a significant improvement in the quality and information content of the lead finding process. We will discuss how virtual screening using bioactivity profiles and in silico MOA elucidation bridges the gap between a phenotype and a target.

11:35

Whole Organism Chemical Screens to Identify Modulators of FGFs

Michael Tsang, Associate Professor, Department of Developmental Biology, University of Pittsburgh

Fibroblast Growth Factors (FGFs) are a large family of secreted proteins that activate the RAS/MAPK pathway to regulate a multitude of process including cellular growth and differentiation. Identifying small molecules that modulate this pathway will be useful in dissecting the role of FGFs disease and normal physiology. Over the past several years we have developed an in vivo high-throughput chemical screen to identify novel small molecules that modulate FGF signaling using transgenic zebrafish embryos. Chemical screens using zebrafish embryos are the only vertebrate animal model where high throughput screens can be performed. The embryos are around 1mm in length allowing for arraying into multi-well plates and transparent, visualization of fluorescent proteins expressed under transgene control aid in both reproducibility and quantification.

We established a transgenic zebrafish line that reports on FGF activity by using green fluorescent protein (GFP) as a read-out for FGF signaling in embryos. Transgenic embryos were utilized in a drug discovery screen to identify compounds that enhanced FGF signaling as potential agents for regenerative therapy. (E)-2-Benzylidene-3-(cyclohexamino)-3H-inden-1-one (BCI) was identified as a compound that increased GFP expression in transgenic embryos. Subsequent experiments including molecular docking studies revealed that BCI is an allosteric inhibitor of a feedback regulator of FGFs, DUSP6. The identification of BCI has enabled developmental studies to determine the role of Dusp6 in cardiac development and regeneration.

1) High-throughput in vivo chemical screen development
2) Strategies to identify targets of hits
3) Agents for regenerative therapy
 

 12:00

FEATURED PRESENTATION

Integrating Novel Technologies to Identify Small-Molecules That Drive Translational Research and Therapeutics in Cardiovascular Disease

Michelle Palmer, Director Discovery and Preclinical Research, Broad Institute of Harvard and MIT

Advances in human genetics have lead to new drug discovery strategies that may lower the rate of attrition when translated to human trials. Insights from these studies point to targets that have traditionally been challenging for small-molecule therapeutics. Identification of drugs to modulate targets where knowledge of the targets function in disease is poorly understood requires innovation in chemistry, phenotypic cell-based assays and target identification studies. We have integrated technology across all aspects of lead identification in an effort to realize the benefit of the genes to drugs approach in cardiovascular disease. Using the insights derived from GWAS in up to 100,000 individuals, we have identified multiple genetic loci associated with LDL-C, HDL-C, and/or triglycerides. Supporting data from both mouse and additional human data of one of these loci—TRIB1, indicates that pharmacological upregulation of hepatic TRIB1 expression would result in decreased LDL-C, increased HDL-C, and decreased triglycerides, together resulting in decreased risk of MI in humans. We have identified novel scaffolds from our diversity oriented synthesis compound collection using a phenotypic cell based screening strategy that upregulate TRIB1 expression as well as a decrease in PCSK9 expression in liver cells. The unique properties of this screening collection have facilitated rapid SAR and a fast entry into target ID. Progress on this novel drug discovery target will be presented.

12:25

Lunch Provided By GTC

2:00

Conference Concludes

Attend ALL GTC Conferences for One Year for only $3,995 ($1,990 for Acad/Govt).
Click here to sign up!