Wednesday, June 8th
8:30 Chairperson’s Remarks
Erica Evans, Ph.D., Principal Scientist, Avila Therapeutics, Inc.
8:40 Case Study from AstraZeneca
Stephanos Ioannidis, Ph.D., Principal Scientist I, Cancer Chemistry, AstraZeneca
9:05 Case Study from Incyte
Jordan S. Fridman, Ph.D., Director, Pharmacology, Incyte Corp.
9:30 Bruton’s Tyrosine Kinase from Bench to Bedside: Covalently Silencing B Cells with AVL-292
Erica Evans, Ph.D., Principal Scientist, Avila Therapeutics, Inc.
Bruton’s tyrosine kinase (Btk) plays a crucial role in the development and activation of B cells through the BCR signaling pathway and represents an exciting new target for therapeutic intervention in diseases characterized by inappropriate B cell activity. We will describe a targeted covalent drug design strategy that has enabled the discovery of a potent and highly selective inhibitor of Btk, AVL-292, which has recently entered clinical development.
9:55 Application of Functional Screening using Cultured Human Mast Cells for the Discovery and Optimization of SYK Kinase Inhibitors Leading to Fostamatinib
Rajinder Singh, Ph.D., Head, Medicinal Chemistry, Rigel Pharmaceuticals, Inc.
Use of cultured human mast cells in high throughput screening for identification of hits inhibiting immunoglobulin E (IgE) mediated activation of Fc receptor signaling leading to downstream inhibition of degranulation. Application of this paradigm to structure activity relationship (SAR) to one particular scaffold generated potent analogues and the discovery of orally bioavailable R406. Importantly R406 also blocks SYK-dependent Fc receptor mediated activation of monocytes, macrophages and neutrophils and B-cell receptor (BCR)-mediated activation of B lymphocytes. Formulation properties of R406 were further enhanced via synthesis of R788, fostamatinib, which has advanced to Phase 3 studies.
10:20 Networking Coffee Break in the Exhibit Hall with Poster Viewing
11:00 Featured Speaker
Highly Selective Brain-Penetrant Inhibitors of Glycogen Synthase Kinase 3-β for Alzheimer’s Disease
Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer
Glycogen synthase kinase 3-β (GSK-3β) is an attractive target for the treatment of Alzheimer’s disease. However, it has been a challenge to develop potent kinase inhibitors that are brain-penetrant because of almost the orthogonal attributes required for these two activities. We will discuss the discovery of a selective GSK-3β inhibitor that demonstrates pharmacological modulation of phosphorylated-Tau in rat brain.
11:30 Elucidating the Role of LRRK2 in Parkinson’s Disease
Greg Cuny, Ph.D., Assistant Professor, Harvard NeuroDiscovery Center, Brigham & Women’s Hospital and Harvard Medical School
Leucine-rich repeat kinase 2 (LRRK2) has recently emerged as a potential contributor to Parkinson’s disease pathophysiology. This presentation will provide a brief overview of LRRK2 biology and chemistry, highlight some of the challenges in tackling LRRK2 as a drug discovery target and illustrate several strategies at identifying modulators of LRRK2 kinase activity.
12:00 pm Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own
1:10 Chairperson’s Remarks
Andrew C. Good, Ph.D., Distinguished Scientific Fellow, Medicinal Chemistry, Genzyme Corp.
1:15 Discovery of Crizotinib (PF-02341066)-A c-Met/ALK Dual Inhibitor for Oncology Applications
Jean Cui, Ph.D., Associate Research Fellow, Oncology Medicinal Chemistry, Pfizer, Inc.
Crizotinib (PF-02341066) has shown remarkable efficacy for lung cancer patients with EML4-ALK fusion gene and is currently in Phase III clinical trials. Crizotinib is created as a c-Met/ALk dual inhibitor using structure-based drug design in combination with medicinal chemistry principles.
1:45 A Role for Hydration in Interleukin-2 inducible T Cell Kinase Selectivity
Ronald Knegtel, Ph.D., Research Fellow I, Molecular Modeling, Vertex Pharmaceuticals (Europe) Ltd.
A series of Itk inhibitors that achieve selectivity through the introduction of a single, solvent exposed aromatic nitrogen atom without direct interactions with the enzyme is reported. By analyzing active site hydration using WaterMap, the selectivity profile can be explained in terms of the replacement of a thermodynamically unfavorable water molecule by the inhibitor and improved hydration of the bound ligand. This hydration site was successfully used to enrich virtual screening results in their content of selective Itk inhibitors.
2:15 Overcoming Drug-Resistant Mutations in Kinase Drug Discovery: Applying Lessons from Ponatinib (AP24534)
David C. Dalgarno, Ph.D., Vice President, Research Technologies, ARIAD Pharmaceuticals, Inc.
Ponatinib (AP24534) is a novel BCR-ABL inhibitor that inhibits both native and mutant BCR-ABL, including the T315I gatekeeper mutation, and hence acts as a pan-BCR-ABL inhibitor. We recently analyzed the structural basis for this pan-BCR-ABL activity. Here we discuss this analysis and how it can be applied to other kinase targets exhibiting mutation-based resistance, and how the lessons from ponatinib can be applied to the design of other mutant kinase inhibitors.
Sponsored by
2:45 Interrogating the Kinome with HotspotTM Kinase AssaysStephen A. Parent, Ph.D., Director of Business Development, Reaction Biology CorporationRBC provides drug profiling and screening services using HotSpot technology, a high-throughput radioisotopic screening platform with more than 370 kinases. We will describe its application to kinase inhibitor development and kinase inhibitor selectivity.
3:00 Networking Refreshment Break in the Exhibit Hall with Poster Viewing
3:30 Structure-Guided Fragment-Based Drug Discovery for Protein Kinase Targets
Stephen K. Burley, M.D., D.Phil., Distinguished Lilly Research Scholar, Lilly Biotechnology Center, Eli Lilly and Company
4:00 How Molecular Dynamics Simulation May be Applied in Structural Based Design of Kinase Drugs
Yibing Shan, Ph.D., Senior Scientist, Chemistry and Biology, D. E. Shaw Research
The understanding of the extensive conformational heterogeneity of protein kinases is crucial to the understanding of kinase drugs’ binding and specificity. To this end, long molecular dynamics (MD) simulations, which for the first time reached the relevant timescale of micro- to milli-second, may prove a powerful tool. Our MD study of Abl, Src, and EGFR kinases will be discussed as examples of such effort in its early stage.
4:30 Recent Experience Establishing a New Lead ID Capability to Pursue Oncology Kinase Targets
Hans-Peter Biemann, Ph.D., Associate Scientific Director, in vitro Biology, Genzyme Corporation
Genzyme’s small molecule discovery unit has incorporated fragment-based and x-ray structure-assisted technologies over the last three years. Ligands of 150-250 Daltons have undergone structure-assisted elaboration to identify novel potent and selective inhibitors of tyrosine and ser/thr kinases, including Pim-1. We progressed a tyrosine kinase to late lead optimization in 2.5 years and newer projects have productively commenced outside of the kinase and oncology sectors. This evolution of our HTS-based drug discovery unit to a multi-platform format enables us to address a number of target classes more expediently than before.
5:00 Longstanding Kinase Contributor Panel: Structure-Based Kinase Inhibitor Design
Topics
Insights correlating kinase selectivity and toxicity
Using co-crystal structures to generate novel kinase scaffolds
Using structure to improve selectivity alongside potency
Andrew C. Good, Ph.D., Distinguished Scientific Fellow, Medicinal Chemistry, Genzyme Corp.
Kinase Bio: Highly experienced computational chemist involved in 3 projects that have brought compounds to the clinic. Exposure to multiple kinase projects at GlaxoWellcome, Bristol-Myers Squibb and Genzyme. Currently leading primary Genzyme kinase oncology project, shepherding the program from hit id through to late stage lead optimization.
Ravi G. Kurumbail, Ph.D., Research Fellow and Structural Biology Laboratory Head, Pfizer
Kinase Bio: Experience in structure-based drug design in over half a dozen kinase projects in the pharmaceutical industry; have contributed to the development of clinical candidates; experience in evaluation of kinase inhibitors for CNS indications; championed a kinase project for Alzheimer’s disease; trained as a protein X-ray crystallographer; currently leading a structural biology lab at Pfizer.
Dirksen Bussiere, Ph.D., M.B.A., Director, Structural Chemistry, Novartis Institutes for BioMedical Research
Kinase Bio: Fifteen years experience in structure-based drug design, including more than ten projects targeting kinases for diabetes and cancer, several of which led to compounds currently in development; trained in protein biochemistry, biophysics, structural biology, and computational chemistry/biology; currently leading a structural biology group at Novartis.
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5:30 Close of Day