Tuesday, June 5
8:20 am Chairperson’s RemarksKelvin Lam, Ph.D., Vice President, Assay Services, Blue Sky Biotech
8:30 Pathway-Based Identification of Biomarkers for Targeted Kinase Therapeutics
An Chi, Ph.D., Research Fellow, Molecular Biomarkers Department, Merck Research Laboratory
To enable the generation of drug-specific biomarker tools for kinase inhibitors, we discuss a differential phospho-proteomic approach to identify and quantify drug-regulated phosphorylation events. Recent examples of translational strategies for PI3K inhibitors would be highlighted.
9:00 Comprehensive Assay of Kinase Catalytic Activity Reveals Features of Kinase Inhibitor Selectivity and Novel Kinase-Inhibitor Interactions
Jeffrey R. Peterson, Ph.D., Associate Professor, Cancer Genetics and Signaling, Fox Chase Cancer Center
In the November issue of Nature Biotechnology, we reported the largest analysis of small molecule inhibition of kinase catalytic activity, testing 178 compounds against 300 recombinant human protein kinases using a high-throughput form of a substrate phosphorylation assay. The inhibitors tested include FDA-approved drugs, compounds in the clinical pipeline, and research tool compounds. Many off-target interactions were observed with seemingly unrelated kinases, revealing how large-scale profiling can identify multitargeted inhibitors of specific, diverse kinases. I will make the case for large-scale inhibitor profiling as a new approach to screening for drug candidates and will highlight many novel and surprising inhibitor-kinase interactions revealed by this study.
9:30 No Patent Left Behind - A Prerequisite in Kinase Inhibitors Competitive IntelligenceParthiban Srinivasan, Ph.D., CEO & President, Parthys Reverse InformaticsKinase research is accelerating every year. Retrieving complete list of kinase patents to remain up-to-date is a challenge. Patents use non-standard nomenclature. Searches performed with our kinase synonyms dictionary, retrieved even the obfuscated patents, generating actionable reports for you!
9:45 Sponsored Presentation (Opportunity Available)
10:00 Coffee Break in the Exhibit Hall with Poster Viewing
10:45 Activation-State Dependent Conformational Differences in Protein Kinases and the Role of Hydrophobic Motifs in Inactive Kinases: Lessons Learned in Drug Discovery and Optimization
Mark Ashwell, Ph.D., Vice President, Chemistry, ArQule
The presentation will describe the utilization of a new understanding of the role of hydrophobic residues within the ATP-binding cleft of inactive protein kinases in order to discover novel inhibitors. Strategies will be presented and discussed for the identification and optimization of small molecule inhibitor of several kinases e.g., c-Met, FGFR, AKT and others. Characterization of the molecular interactions with inactive kinases will be described using biophysical, biochemical and cell-based assays together with X-ray crystallographic and mutational studies.
11:15 Kinase Virtual Screening with Accuracy Comparable to Experiment
Eric Martin, Ph.D., Director, Computational Chemistry, Global Discovery Chemistry, Novartis Institutes for BioMedical Research
Three novel kinase virtual screening methods achieve unprecedented speed and accuracy by including massive amounts of IC50 and structural data from previous kinase targets into models for each new kinase: the 2D “Profile-QSAR” meta-QSAR, the Kinase-Kernel chemogenomic model, and 3D Surrogate AutoShim docking method. Between the 3 methods, 2 billion activity predictions have been made for 4 million internal and commercial compounds across 500+ kinases, so kinase virtual screening is now a table lookup. Applied to over 3 dozen active Novartis projects, at all stages of discovery, with external R2=0.35–0.7 and enrichments of 20x–70x. AutoShim and Profile-QSAR have also been extended to Serine and Cystine Proteases.
11:45 Identification of Novel Non ATP – Competitive Inhibitors against Human MAP Kinase Kinase1 (MEK1) and MEK2
Rambabu Gundla, Ph.D., Principal Scientist, Informatics, GVKBIO Sciences Pvt Ltd.
Virtual screening models were generated and validated utilizing a set of known human MAP kinase kinase1 (MEK1) and MEK2. The virtual screening models were successfully employed to discover a set of structurally diverse Non ATP – Competitive Inhibitors with growth inhibitory activity against MEK1 and MEK2. A search of a 3D database containing 6MM small molecules using the virtual models retrieved 734 potential hits. Of the 734 hits, 62 were selected for testing in vitro on the basis of structural novelty and desirable drug-like properties. Thirteen compounds inhibited with IC50 values <10 μM. These lead compounds have desirable physicochemical properties and are excellent candidates for further optimization.
12:15 pm Luncheon Presentation
Next Generation Assay Platform For The Direct Measurement of Compound Binding To Kinase Targets in Intact CellsTom Wehrman, Ph.D., Vice President, Research & Development, DiscoveRx Assays that directly measure target binding in cells can be of great utility in translating in vitro data to more biologically relevant models. However, for a number of target classes these assays are difficult/impossible to make, may require prolonged compound incubation times, or offer only an indirect read-out that may be affected by other cellular factors. To overcome these limitations we have developed a number of cellular assay platforms that detect protein translocation, protein interactions and protein stabilization based on enzyme fragment complementation. In this work we present a new technology for directly monitoring the cellular potency of test compounds. This system detects the binding of a small molecule to a protein target in intact mammalian cells by monitoring changes in protein structure and stability. Using this system we have profiled a number of kinase targets and show that the system can detect allosteric as well as ATP-competitive inhibitors and can appropriately rank-order compounds for cellular potency. Since the system is activity-independent, HTS-friendly cell-based assays can be developed for kinases where the substrates are not known or antibodies have not been developed greatly expanding the number of immediately tractable kinase targets.
1:35 Chairperson’s RemarksKelvin Lam, Ph.D., Vice President, Assay Services, Blue Sky Biotech
1:40 Template-Directed Assembly (TDATM) is an Enabling Technology to Overcome the Challenges of Targeting Membrane-Associated KinasesKelvin Lam, Ph.D., Vice President, Assay Services, Blue Sky BioServicesMembrane associated kinases are challenging class of targets because they are located and function adjacent to the hydrophobic natural lipid-bilayer environment. Traditionally, one studied these target class by isolating soluble catalytic domains, which lacks the proper physiological context. As a proof of principle TrkA was selected to validate the technology. TrkA receptor, which is part of the larger RTK (Receptor Tyrosine Kianse) receptor family, is activated by neurotrophins and implicated in neurodegeneration, pain, and cancer. We screened against a compound library and identified compounds with higher potency. We will show concordance between primary assay and secondary cell-based assays, including High Content Screen (HCS) assay. We will also discuss additional applications for the technology.
2:10 Inhibiting PI3K for Treating Inflammatory Diseases
Stephen J. Shuttleworth, Ph.D., CSO, Karus Therapeutics, Ltd.
2:40 Quantum Mechanical Probes: Discovery of Selective Kinase Inhibitors
Ting Zhou, Ph.D., Scientist, Biochemistry, University of Zurich
3:10 Refreshment Break in the Exhibit Hall with Poster Viewing
4:00 To Develop Novel Drak2 Inhibitors for the Treatment of Autoimmune Diseases
Jiangping Wu, Ph.D., Professor of Medicine, Medicine, University of Montreal
Drak2 is a novel therapeutic target for certain autoimmune diseases, and it is a safe one as Drak2 gene knockout mice have no gross anomalies. We obtained 2 highly potent inhibitors at less than 30 nM in IC50, after screening of 570,000 compounds. We also identified p70S kinase as Drak2’s substrate. This raises an interesting possibility that Drak2 and mTORC1 share a part of their signaling pathway.
4:30 The Resurgence of Covalent Drugs
Juswinder Singh, Ph.D., Founder & CSO, Celgene Avilomics Research
5:00 Close of Day Two