2015 Archived Content
Kinase inhibitors have over a decade of success as targeted oncology therapies (both antibody and small molecule-based) and more recently as orally-available inhibitors for inflammation. Fueling activity in the small molecular kinase drug discovery arena are greater amounts of structural information available for many kinases and richer biological pathway knowledge gleaned from kinase inhibitors aborted in drug development, but re-deployed to probe biological pathway questions. CHI’s Kinase Inhibitor Discovery meeting convenes discovery biologists and chemists to discuss the newest strategies for kinase inhibitor design, to stay abreast of oncology, inflammation and CNS-related kinase inhibitors in the clinic and hear about kinases emerging from basic research whose medical relevance has been validated.
Final Agenda
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Wednesday, September 23
11:30 am Registration
12:55 pm Plenary Keynote Program
2:40 Refreshment Break in the Exhibit Hall with Poster Viewing
3:25 Chairperson’s Opening Remarks
Suvit Thaisrivongs, Ph.D., Head, Immunoscience Chemistry, Pfizer Worldwide Medicinal Chemistry
3:35 ‘Back to Front’ Design of Potent and Selective DDR1/2 Inhibitors
Valerio Berdini, Ph.D., Associate Director, Computational Chemistry, Astex Pharmaceuticals
The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket of the kinase. Modeling based on crystal structures of potent kinase inhibitorsfacilitated the “back-to-front” design of potent DDR1/2 inhibitors. Optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2.
4:05 Conformation-Specific Kinase Inhibitors
Scott Foster, Ph.D., Post-Doctoral Fellow, Laboratory of Shiva Malek, Discovery Oncology, Genentech
Kinase domain mutations are drivers in many types of cancer. While the majority of oncogenic point mutations function in part by destabilizing the inactive conformation, it is becoming clear that altering the C-Helix region to directly promote the active conformation provides an alternative mechanism of activation. Our work underscores the importance of conformation specific inhibitors to target mutationally activated kinases.
4:35 Binding Studies of Type I, Type II and Type III Kinase Inhibitors against Bcr-Abl Kinase using TruBind™ Back-Scattering Interferometry
Scot Weinberger, Executive Vice President, Research and Development, Molecular Sensing, Inc.
Abnormal kinase activity contributes to the onset of cancer. Most kinase inhibitors are Type I inhibitors that bind to the ATP binding site or Type II that bind partially to the ATP site. TruBind(tm) technology studied the interaction of Type I, II, and III (allosteric) inhibitors of Bcr-Abl kinase. Binding studies of class I, II, and III inhibitors confirmed target engagement and provided inhibitor affinity assessment.
5:05 Refreshment Break in the Exhibit Hall with Poster Viewing
5:40 Self-Assembling Bivalent Inhibitors: A Modular Strategy for Improving Potency and Selectivity of Kinase Inhibitors
Jason Thomas, Ph.D., Investigator, Developmental and Molecular Pathways, Target Identification Proteomics, Novartis Institutes for Biomedical Research, Inc.
Here, we present a modular chemical genetic strategy for accessing bivalent kinase inhibitors. Starting from a promiscuous ATP-competitive inhibitor, we show that it is possible to confer high selectivity by tethering the inhibitor to an antibody mimetic fused to a self-labeling protein. In addition to establishing enhanced potency and selectivity of various bivalent inhibitors, we demonstrate that a bivalent inhibitor is able to readily assemble in cells and directly inhibits its target kinase.
6:10 De-Convoluting Kinase Inhibitor Cardiotoxicity Using Impedance-Based Assays
Sarah D. Lamore, Ph.D., Discovery Safety Scientist, Drug Safety and Metabolism, AstraZeneca
Kinase inhibitor (KI) promiscuity and the complexity of cardiac physiology has been a persistent hurdle in unraveling the specific kinases contributing to functional cardiotoxicity. We used impedance technology to interrogate the effects of KI with known selectivity profiles on stem cell-derived cardiomyocytes and identified a small set of sentinel kinases useful for screening. This novel approach and the relationships discovered herein will enable a rational strategy to predict and design-in safety early in drug discovery
6:40 Close of Day
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Thursday, September 24
7:30 am Registration
8:00 Interactive Breakfast Breakout Discussion Groups
This interactive session provides conference delegates and speakers an opportunity to choose a specific roundtable discussion group to join. Each group has a moderator to ensure focused discussions around key issues within the topic. This format allows participants to meet potential collaborators, share examples from their work, vet ideas with peers, and be part of a group problem-solving endeavor. The discussions provide an informal exchange of ideas and are not meant to be a corporate or specific product discussion.
Blood Brain Barrier (BBB) Penetration with Kinase Inhibitors
Paul Galatsis, Ph.D., Senior Principal Scientist, Worldwide Medicinal Chemistry, Pfizer
- Compound design strategies: physicochemical properties,in silico tools
- Methods for assessing brain penetration: preclinical (Kpuu), clinical (PET tracers), translational biomarkers of central exposure
- Safety issues: minimizing peripheral off-target exposure, selectivity, Ceff
In vitro to In Vivo challenges
John Robinson, Ph.D., Senior Research Investigator, Medicinal Chemistry, Array Biopharma, Inc.
- Assessing selectivity
- Translating cellular readouts
- Combining kinase inhibitors for cancer
Fragment-based Screening for Kinase Inhibitors
Valerio Berdini, Ph.D., Associate Director, Computational Chemistry, Astex Pharmaceuticals
- Selectivity (vs. other kinases)
- Novelty (in terms of IP space)
- Fragments outside the hinge
8:45 Chairperson’s Remarks
John Robinson, Ph.D., Senior Research Investigator, Medicinal Chemistry, Array Biopharma, Inc.
8:55 KEYNOTE PRESENTATION: Clinical Experience and Preclinical Insights into Kinase Inhibitor and Immunotherapy Treatments for Cancer
Jason J. Luke, M.D., FACP, Assistant Professor of Medicine, Melanoma and Developmental Therapeutics Clinics, University of Chicago
Immunotherapy is emerging as a treatment in many cancers however kinase directed therapies also have a role. An imperative then is to understand the optimal combination of these approaches. Some combinations will be developed solely on clinical availability however a rational paradigm would be based on synergy between treatments or identifying new “targeted” therapies that could augment the immune response. I will also go over results from a recent study in a melanoma mouse model that shows the combination of BRAF inhibitor dabrafenib and MEK inhibitor trametinib can synergize with adoptive cell therapy or anti-PD-1 therapy. The combination increases melanoma tumor antigen expression and antigen recognition by T cells, increases T cell homing to the tumors, and preserves effector functions. Three clinical trials are ongoing to test this triple combination.
9:55 Effect of Targeted Therapies on Anti-tumor Immunity
Taha Merghoub, Ph.D., Associate Biologist, Immunology, Memorial Sloan Kettering Cancer Center
10:25 Coffee Break in the Exhibit Hall with Poster Viewing and Poster Winner Announced
11:10 Identification of Novel, in vivo Active Chk1 Inhibitors Using Structure-Guided Drug Design
Stephen Stokes, Principal Scientist, Chemistry, Vernalis Research
This will be the first report of the structure of V158411, a novel inhibitor of the DNA-damage cell-cycle checkpoint protein Chk1. Inhibiting Chk1 enhances the anti-tumor activity of DNA-damaging chemotherapy drugs. Fragment elaboration by structure guided design was used to identify and develop a novel series of Chk1 inhibitors culminating in the identification of V158411, a potent ATP-competitive inhibitor of the Chk1 and Chk2 kinases.
11:40 Identification and Optimization of a Novel Class of Checkpoint Kinase 1 Inhibitors
Huifen Chen, Ph.D., Senior Scientist, Discovery Chemistry, Genentech, Inc.
Checkpoint kinase 1 (Chk1) is a Ser/Thr protein kinase and a key mediator in the DNA damage-induced checkpoint network. It is hypothesized that inhibition of ChK1 might enhance the effectiveness of existing DNA-damaging chemotherapeutic agents in the treatment of cancer. The discovery and lead optimization of a novel class of Chk1 inhibitors will be presented.
12:10 pm Selective TTK Inhibitors with Long Target Residence Time and Potent Anti-Tumor Activity
Guido Zaman, Ph.D., Managing Director & Head, Biology, NTRC
Triple negative breast cancers are characterized by a high degree of chromosome instability and overexpress TTK. To explore the potential of TTK as a targeted therapy, we developed a highly potent and selective TTK inhibitor. Combination with docetaxel resulted in tumor remission and increased survival in a genetic mouse model.
12:40 Kinase Profiling Strips for Targeted and Flexible Kinase Inhibitor Profiling
Hicham Zegzouti, Ph.D., Senior Research Scientist, Research and Development, Cellular and Biochemical Technologies, Promega Corporation
Kinase profiling that can be simply implemented in-house would obviate logistical inconveniences, delays and confidentiality concerns associated with outsourcing. We developed a pre-configured profiling system for 112 kinases with standardized activities. Using this system, we could quickly and easily generate selectivity profiles with any size kinase panels, and identify compound promiscuity within the kinome.
12:55 Session Break
1:00 Luncheon Presentation: HP Inkjet Technology for Improved Kinase Assay Results
Ken Ward, Ph.D., New Product Development, HP Inc.
HP inkjet technology is now being used around the world to easily and precisely dispense both small molecule and biological compounds directly into assay ready plates. Join us for presentation of and active dialog about research case studies. Learn how fellow drug discovery researchers are accelerating learning through an improved understanding of drug dose response, MOA and drug-drug synergies.
1:40 Refreshment Break in the Exhibit Hall with Poster Viewing
2:15 Chairperson’s Remarks
Seng-Lai "Thomas" Tan, Ph.D., Senior Director, Immunology, FORMA Therapeutics
2:20 Targeting JAK3 with Covalent Inhibitors
Chris Burns, Ph.D., Laboratory Head, Chemical Biology Division, Walter and Eliza Hall Institute, Australia
Selective inhibition of JAK3 has promise as treatment for auto-immune and inflammatory diseases because JAK3 expression is limited to cells of the immune system. Other members of the JAK family are widely expressed. Discussion on the optimization of JAK3-targeted agents has been embargoed until this year due to a multi-year collaboration with Novartis. The optimized compounds represent the most selective and potent JAK3 inhibitors reported.
2:50 JAK-1 Selective Clinical Candidate for the Treatment of Autoimmune Diseases
Suvit Thaisrivongs, Ph.D., Head, Immunoscience Chemistry, Pfizer Worldwide Medicinal Chemistry
The presentation will describe the discovery program of our JAK1 selective inhibitors and the identification of our clinical candidate, currently in Phase 2 clinical development. The discussion will cover our structure-based medicinal chemistry design and our JAK platform expertise from Tofacitinib clinical data to advance our discovery research program.
3:20 Session Break
3:30 Characterization of Novel PI3Kdelta Inhibitors as Potential Therapeutics for Systemic Lupus Erythematosus
Roland Grenningloh, Ph.D., Director Preclinical Pharmacology, TIP Immunology, EMD Serono Research & Development Institute, Inc
We identified selective PI3Kδ inhibitors that blocked B-, T-, and plasmacytoid dendritic cell activities and were efficacious in an IFNα-accelerated mouse SLE model. Efficacy correlated with reduced immune complex deposition, inflammation, fibrosis and tissue damage in the kidney. Using a pharmacodynamics/pharmacokinetic/efficacy model we established that a sustained PI3Kδ inhibition of 50% is sufficient to achieve full efficacy in this disease model.
4:00 Discovery and Preclinical Profiling of LRRK2 Kinase Inhibitors for the Treatment of Parkinson’s Disease
Paul Galatsis, Ph.D., Senior Principal Scientist, Worldwide Medicinal Chemistry, Pfizer
We will communicate our strategy for designing brain penetrant kinase inhibitors and share medicinal chemistry insights into targeting the key cause of familial Parkinson’s disease, LRRK2. We will provide examples of compounds that have in vivo activity at less than 1 mg/kg oral dosing.
4:30 ARRY382: Exploring the Role of CSF1R in Immuno-Oncology
John Robinson, Ph.D., Senior Research Investigator, Medicinal Chemistry, Array Biopharma, Inc.
Colony Stimulating Factor (CSF) 1 drives macrophage –mediated immune suppression in the tumor microenvironment. Therefore CSF1 inhibitors have the potential to augment immune responses when combined with established tumor immuno-therapeutics such as anti-PD-1 and anti-CTLA4. We present the design, discovery and phase 1 results of ARRY-382, a potent, selective CSF1R kinase inhibitor.
5:00 Close of Conference
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