Tuesday, June 22
8:15 BREAKFAST BREAKOUT SESSION WITH MODERATED TOPIC DISCUSSIONS
Topic 1: Non-ATP competitive KinasesModerator: Thomas Chan, CSO, ArQule, Inc.
Topic 2: Selectivity - multikinases vs selective kinasesModerator: Yogesh Sabnis, Ph.D, Pfizer Global R&D, Sandwich, Kent, United KingdomTopic 3: Structure-Based Drug DesignModerator: TBATopic 4: Novel Applications beyond CancerModerator: D. Martin Watterson, Ph.D., J.G. Searle Professor & Co-Director, Center for Drug Discovery & Chemical Biology, Northwestern University
Specificity and Efficacy
9:25 Chairperson’s Remarks
9:30 Novel Peptide Modulators of Protein Kinases
James Tomlinson, Ph.D., Associate Scientific Director, Molecular and Integrative Pharmacology, KIA Pharmaceuticals, Inc.
Protein kinases govern many of the critical signaling pathways in biological systems. It is known that many of these kinases regulate signaling via coordinated congregation into heterologous protein assemblages, resulting in substrate phosphorylation, and requisite pathway control. We have designed a number of peptide modulators which target these assemblages and which demonstrate kinase specificity, and efficacy in disease models.
10:00 Networking Coffee Break, Poster and Exhibit Viewing
10:45 Second Generation Kinase Inhibitor Therapeutics - Specificity and Individual Mechanism of Action in Clinical Use
Oliver Hantschel, Ph.D., Directors Group, CeMM Center for Molecular Medicine, Austrian Academy of Sciences
11:15 Clinical Pharmacokinetics of the BCR-ABL Tyrosine Kinase Inhibitor Nilotinib
Ophelia Yin, Ph.D., FCP, Clinical Pharmacology Expert, Novartis Pharmaceuticals Corporation
11:45 pm Lunch on Your Own
1:40 Chairperson’s Remarks
Yogesh Sabnis, Ph.D, Pfizer Global R&D, Sandwich, Kent, United Kingdom
Optimizing Leads and Selectivity
1:45 Residence Time and Thermodynamics: How Novel High-Throughput Binding Assays Impact Drug Discovery
Lars Neumann, Head of Assay Development & Screening, proteros biostructures GmbH
Novel homogeneous high throughput binding assays deliver unprecedented volumes of kinetic and affinity (Kd) data for large amounts of compound/fragment-target interactions thereby opening up new avenues in drug discovery. For the first time, the concept of SAR can be expanded into the concept of SKR (structure kinetic relationship) on a broad scale producing drugs with tailor-made binding kinetics. Affinity based selectivity profiling can be replaced by the pharmaco dynamically more relevant kinetic based selectivity profiling. Van´t Hoff analysis reveals the driving forces and the nature of compound binding by quantifying entropy and enthalpy changes upon binding for hundreds of compounds in parallel. In several show cases, we demonstrate the impact of high throughput kinetic measurements on lead discovery.
2:15 Selected Oral Poster Presentations:3-Amino-4-Oxy-Pyrazolopyridines: Inhibitors of the Kinase Met with In Vivo Efficacy in TGI Studies
Allen Thomas, Ph.D., Research Investigator, Array BioPharma
Ubiquitination-Mediated Deactivation of Akt by Dual Function Inhibitor Targeting PH Domain
Hakryul Jo, Ph.D., Children's Hospital Boston/HMS
2:45 Oncodesign Translational Drug Discovery Process: Addressing the Innovation Needs in Oncology
Jan Hoflack, Ph.D., Vice President, Discovery, Oncodesign
Despite major advances in translational methods, oncology drug discovery remains a largely sequential process, in most cases starting from a molecular target with some initial but often limited relevance to the disease. We have developed and validated a flexible and iterative “Translational Drug Discovery Process”, in which multiple translational research platforms create a tight link between molecule development and cancer pathophysiology. These platforms include cellular models, in vivo tumourgrafts, phenotypic models and a multi-modality imaging platform. Recent additions that are based on fresh patient-derived tumour tissue include ex vivo 3D models and low passage tumourgrafts. We have also initiated a program to discover 18F-labeled kinase inhibitor based biomarkers/imaging tracers for use in PET applications. Our research base was recently completed with the addition of a diverse collection of potent and selective kinase inhibitors and the associated proprietary chemical technology. The power of our translational approach will be demonstrated by the story of the discovery of our 2 lead kinase inhibitors that have recently entered IND-enabling studies.
3:15 Networking Refreshment Break, Poster and Exhibit Viewing (last chance)
4:00 Allosteric Kinase Inhibitors: Opportunities Beyond the Kinase Domain
Jeffrey Peterson, Assistant Professor, Cancer Genetics and Signaling, Fox Chase Cancer Center
Identifying selective ATP-competitive kinase inhibitors is a major challenge due to the evolutionary conservation of the ATP-binding pocket among kinases. Allosteric inhibitors represent an alternative approach that may provide greater target selectivity. Kinases frequently contain separate domains that regulate kinase location and/or catalytic activity and these domains may offer opportunities for allosteric kinase inhibition. P21-activated kinase (Pak) is an attractive target in oncology and inflammation that contains an autoregulatory domain distinct from the kinase domain. I will describe the development of an HTS screen to capture allosteric Pak inhibitors and the identification of a small-molecule inhibitor that prevents Pak activation by targeting the Pak regulatory domain with high selectivity.
4:30 Looking Beyond Potency – A Kinetic Perspective on Inhibition in Kinases
Achieving potency and attainment of sufficient drug concentration at the site-of-action to elicit the desired response with tolerable toxicity is a key objective for drug discovery programs. An inhibitor usually achieves potency by competing with endogenous ligands or substrates at a structurally defined binding site, and for a competitive inhibitor this event is mutually exclusive. Improving potency by maximizing the interactions between the constituent parts of the target and inhibitor are key to the successful design of potent inhibitors. However, a potential drawback of competitive inhibition is that the potency can be diminished by mass-action competition with high concentrations of a natural substrate such as ATP. One way of avoiding competition between inhibitor and substrate is to achieve non-equilibrium mechanisms of inhibition. Here, we focus on slow off-set kinetics as a means of achieving non-equilibrium inhibition. The importance of on and off rates in designing slow off-set kinase inhibitors and its implications in inhaled therapy will be discussed.
5:00 Expert Panel Discussion: The Challenge of Selectivity
6:00 End of Day 2
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