Tuesday, June 7
8:30 am Chairperson’s Remarks
David H. Drewry, Ph.D., Director, Department of Chemical Biology, GlaxoSmithKline
8:40 Featured Speaker
Resistance to Kinase Inhibitors: Mechanisms, Challenges and Opportunities
Isabelle Dussault, Ph.D., Director, Oncology Research, Amgen
Kinase inhibitors are important medicines for the treatment of several cancer types. Intrinsic or acquired resistance to these medicines, however, has emerged as a significant barrier to clinical efficacy. The identification of several resistance mechanisms has opened the door to the development of next generation molecules. I will discuss examples of resistance mechanisms and future directions for novel kinase inhibitors.
9:10 Kinase Inhibitor Resistance: A Gateway to Drug Combinations
John D. Haley, Ph.D., Senior Research Director, Translational Research, OSI Pharmaceuticals
Receptor tyrosine kinases (RTKs) are key mediators of tumor cell survival, proliferation and migratory pathways, and inhibitors of RTKs have demonstrated anti-tumor efficacy in both the pre-clinical and clinical settings. RTK inhibitor resistance can be elicited through mutation within kinase domains , through pathway redundancy, seemingly through receptor crosstalk, through reciprocal RTK activation and through cell lineage switching.
9:40 The Published Kinase Inhibitor Set: A Resource to Develop Probes for the Untargeted Kinome
David H. Drewry, Ph.D., Director, Department of Chemical Biology, GlaxoSmithKline
Protein kinases are chemically tractable drug targets, yet <10% of the human kinome has been thoroughly explored with selective small molecule inhibitors. It is likely that pharmacological evaluation of the whole kinome will uncover new opportunities for drug discovery. We will describe our strategy to probe the untargeted kinome via compound sharing and pre-competitive collaborations.
Sponsored by
10:10 More Biologically Relevant Characterization of Kinase Inhibitors in a Simplified Assay FormatKurt Vogel, Ph.D., R&D Director, Life TechnologiesIn addition to the facile identification of type I, II, and III kinase inhibitors and measurent of compound on/off rates, this talk will describe the ability to interrogate large, full length kinase proteins, such as RTKs, in a simple assay format.
10:25 Networking Coffee Break in the Exhibit Hall with Poster Viewing
11:10 Use of a High Content Screening Approach to Identify Neuroprotective Protein Kinase Inhibitors
Donald Zack, M.D., Ph.D., Professor, Ophthalmology and Neuroscience, Johns Hopkins University School of Medicine
Using a novel High Content Screening Approach we have identified protein kinase inhibitors (PKIs) that are neuroprotective for retinal neurons, and thus are potential therapeutic leads for the treatment of glaucoma and age-related macular degeneration. One of the most potent compounds identified is the receptor tyrosine kinase inhibitor sunitinib, which was a surprising find because sunitinib was not previously known to have neuroprotective activity, and in fact would be expected to be toxic to neurons. We have also identified other neuroprotective scaffolds with neuroprotective activity, and these are being optimized through a medicinal chemistry approach.
11:40 Longstanding Kinase Contributor Panel – Selectivity & Kinases Today
How much selectivity is enough?
How is selectivity being assessed?
Differing results from in vitro and cell-based screens
Novel screening formats to assess selectivity
Neil Wishart, Ph.D., Associate Director, Abbott
Kinase Bio: Over 10 years of experience leading multiple kinase programs from early hit-to-lead through to candidate status. Successfully navigated a number of kinase-related pitfalls on multiple classes of kinase targets (serine/threonine, tyrosine, pseudo and PI3 kinases) for Oncology and Immunology indications.
Daniel Goldberg, Ph.D., Director, Chemistry, Karos Pharmaceuticals, Inc.
Kinase Bio: Over 12 years of drug discovery experience, many spent in the field of kinase research. My focus has been on both autoimmune and cardiovascular disease targets from hit-to-lead through candidate selection. I have worked to balance the desired kinase selectivity through structure based approaches while being vigilant on maintaining desired drug like properties.
Isabelle Dussault, Ph.D., Director, Oncology Research, Amgen
Kinase Bio: Cancer Biologist, Team Leader and Director of multiple kinase programs. Experience spans from target identification to clinical candidate identification and early clinical development.
John D. Haley, Ph.D., Senior Research Director, Translational Research, OSI Pharmaceuticals
Kinase Bio: Over thirty years of experience in biochemical research. While at OSI, he has worked on multiple discovery and development programs targeting both tyrosine and serine-threonine directed protein kinases. Group is focused on drug target pathway identification, validation and biomarker discovery through a scientific understanding of epithelial-mesenchymal transition and cancer recurrence.
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12:10 pm Lunch on your own
1:30 Chairperson’s Remarks
Kent Stewart, Ph.D., Research Fellow, Abbott
1:40 Featured Speaker
Non-ATP Competitive Kinase Inhibitors: Potential and Limitations
Doriano Fabbro, Ph.D., Head, Kinase Biology, Expertise Platform Kinases, Novartis Pharma AG
Our knowledge on the structural determinants of kinase inhibition by small molecules binding to the ATP pocket has advanced steadily in the past years. Selectivity of ATP directed kinase inhibitors and the limited set of chemotypes targeting the ATP binding site - a highly crowded area- are issues in kinase drug discovery. In this lecture we will review inhibitors for the Abl as well as other kinases that do not bind to the ATP binding site and show improved target selectivity. The use of these inhibitors in various indications as well as in resistance formation will be discussed.
2:10 The Promise and Challenge of Raf Inhibiton
Josette Carnahan, Ph.D., Principle Scientist, Oncology Research, Amgen
B-Raf kinase activating mutations are frequently found in several solid tumors, especially among melanoma patients. Moreover, expression of the most frequent and well studied activation loop mutation, V600EB-Raf results in chronic MAPK pathway activation and tumor cell dependence for survival. As anticipated by an abundance of pre-clinical studies, B-Raf kinase inhibitors have recently shown remarkable clinical promise. However the emergence of resistance suggests that cancer cells rapidly reprogram signaling pathways that are critical for their survival. Understanding this plasticity will be critical to developing therapeutic regimens with more durable responses.
2:40 Discovery of GDC-0068: An ATP-Competitive Selective Akt Inhibitor for the Treatment of Human Tumors
James F. Blake, Ph.D., Principal Research Investigator, Computational Research, Array BioPharma, Inc.
Akt is a serine-threonine kinase, a downstream effector for phosphatidylinositol 3-kinase (PI3K), and comprises three closely related isoforms (Akt1, Akt2, and Akt3). Akt functions as a pivotal node in the PI3K-Akt-mTOR signaling pathway. Strategies for inhibiting Akt activity have included both kinase active site-directed inhibitors and non-ATP-competitive allosteric compounds. Herein, we report on the discovery and pre-clinical characterization of GDC-0068, a novel, potent, highly selective, oral, small molecule ATP-competitive Akt inhibitor. GDC-0068 demonstrates potent inhibition of Akt in biochemical assays and blocks phosphorylation of downstream substrates of Akt in cell-based assays. It induces growth arrest in human cancer cell lines and demonstrated robust antitumor activity in a range of cancer xenograft models, in particular those with activation of the PI3K-Akt pathway.
Sponsored by
3:10 Kinases With a "Glowing" Future?Simon Plyte, Ph.D, Scientific Director, Biology, Congenia Srl / European Institute of OncologyThe IEO is pursuing inhibitors of the spindle assembly checkpoint kinases. A single luminescent assay format is being used to develop both an HTS and IC50 determination assay that permits direct comparison of inhibitors between different kinases.
3:25 Networking Refreshment Break in the Exhibit Hall with Poster Viewing
4:10 Bone Morphogenetic Protein Receptor Kinase Inhibitors
Paul Yu, M.D., Ph.D., Assistant Professor, Division of Cardiology, Brigham and Women’s Hospital, Harvard Medical School
We have developed scaffolds which target the kinases of the Bone Morphogenetic Protein (BMP) type I Receptors, a subset of the Activin Like Kinase family. These compounds effectively inhibit maladaptive osteogenesis, including heterotopic ossification and vascular calcification. BMP signaling is implicated in the oncogenesis, metastasis, or invasiveness of a number of mesenchyme-derived tumors, and is a proposed target of oncologic therapy.
4:40 Next Generation ALK inhibitors and Personalized Medicine: The Next Frontier of Kinase Drug Discovery
Chris Liang, Ph.D., CSO & Executive Vice President, Xcovery, LLC
Recently, crizotinib has shown very impressive efficacy in NSCLC patients with ELM4-ALK fusion proteins. Unfortunately, after only 6-12 months of treatment, most patients develop resistance. Possible reasons for the short duration of efficacy and resistance are analyzed. Next generation of ALK inhibitors are developed to overcome resistance and to more effectively treat a variety of patients with ALK fusion, mutation, and amplification. This example is extended to highlight the importance of matching the right patient with the right inhibitor for most cost-effective treatments.
5:10 Structure-Guided Drug Design and its Use in the Discovery of Kinase Therapeutics
Dirksen Bussiere, Ph.D., M.B.A., Director, Structural Chemistry, Novartis Institutes for BioMedical Research
Structure-guided drug design is an integral part of the modern drug discovery and lead optimization processes. Drug design typically involves promoting favorable enthalpic interactions between lead compounds and the macromolecular target of interest while minimizing the punitive effects of decreased entropy on the system. While the structure-guided drug design process varies between efforts and between companies, ideally it is iterative in nature and relies on the generation of accurate and timely co-structure information, most often by X-ray crystallography, to help inform the generation of new chemical hypotheses and the subsequent synthesis of the next round of novel lead compounds. Because direct visualization of the lead compound(s) in the target or anti-target of interest is possible, this can greatly reduce the demands of a project on available chemistry resources and can also aid in the design of specific compounds. This target:anti-target discrimination is especially challenging in kinase drug discovery, where the target and anti-targets will share significant primary and tertiary homology. The use of structure-guided drug design in kinase lead optimization will be illustrated using examples from projects targeting serine/threonine kinases and tyrosine kinases, including the discovery of TKI258 (Dovinitib) which targets VEGFR, FGFR, and PDGFR kinases. A project targeting a lipid kinase, Phosphatidylinositol-3-Kinase, which led to the discovery of BKM120, will also be presented. The process, starting from gene-to-structure, and the use of co-structure information and molecular modeling in lead optimization will also be outlined.
5:40 Close of Day