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|SUNDAY, NOVEMBER 1
Recommended Short Course*
12:00 pm - 3:00 pm Targeting GPCRs and Ion Channels with Antibodies (SC2)
*Separate Registration Required
TUESDAY, NOVEMBER 3
12:30 pm Registration
2:00 Chairperson’s Opening Remarks
2:10 Keynote Presentation
Safety and Toxicology Challenges on the Way to a Kinase Inhibitor Drug Development
Anja J. Stauber, Ph.D., DABT, Research Advisor, Cancer/Endocrine Safety Assessment, Eli Lilly and Company
A decade ago, kinase inhibitors held great promise for treating unmet medical needs by specifically targeting key regulators of pathways involved in disease while avoiding unwanted side effects. While targeting kinase pathways still hold great promise, challenges exist in developing kinase inhibitors with toxicity profiles that support clinical trials. The focus of this discussion will be on safety and toxicology challenges experienced in kinase inhibitor drug development.
2:40 Developing a Novel Checkpoint Kinase Inhibitor
Sonya Zabludoff, Ph.D. Associate Director, Cancer Bioscience, AstraZeneca R&D
3:10 Aurora A Inhibitor MLN8237: From Discovery to Development
Jeff Ecsedy, Ph.D., Senior Scientist, Moleculor and Cellular Oncology, Millennium, The Takeda Oncology Corporation
3:40 Networking Refreshment Break in the Exhibit Hall
4:20 Title to be Announced
Peter A. Petillo, Ph.D., Senior Vice President, Deciphera Pharmaceuticals, LLC
4:50 Comparison of in vitro and Cellular IC50 Inhibitory Profiles of 7 Clinical Kinase Inhibitors on 16 Oncologically Relevant Kinases
Jan E. Ehlert, Ph.D., Group Leader, Drug Development, ProQinase
For efficient development of kinase inhibitors, cellular phosphorylation assays are becoming increasingly important. Although these assays have the drawback of relatively low throughput and high complexity, they are considered to be less artificial and to reflect the in vivo situation more closely. To evaluate the informative value of cellular phosphorylation assays, we have determined cellular IC50 values for clinical kinase inhibitors Lapatinib, Tozasertib (VX-680), Sorafenib, Sunitinib, Erlotinib, Gefitinib and Vatalanib in parallel on 16 oncologically relevant kinases involved in proliferation, angiogenesis, survival or metastasis. Comparison of cellular IC50 values with in vitro IC50 values determined at different ATP concentrations reveals striking differences for some but not all compounds, supporting the necessity of cellular analyses. Data will be discussed and compared with cellular and in vitro data from literature.
5:20 Identifying Allosteric Modulators of Pyruvate Kinase Orthologs with Quantitative High-throughput Screening
Douglas Auld, Ph.D., Group Leader, NIH Chemical Genomics, National Institute of Health/NHGRI
This talk will illustrate how we identified allosteric modulators of pyruvate kinase orthologs from human, parasitic and bacterial species. The NIH Chemical Genomics Center (NCGC) employs a process called “quantitative HTS” (qHTS) which greatly improves the quality of information that can be derived from HTS by experimentally determining pharmacological parameters such as potency and efficacy on collections of compounds as large as 300K in size. The use of qHTS to define the SAR of both activators and inhibitors of pyruvate kinases will be shown. The compounds identified have given insights into the allosteric regulation of pyruvate kinase and have provided both anti-cancer and anti-parasitic leads.
5:50 Radiosensitize Human Cancer Cells by an scFv against the DNA-Dependent Protein Kinase
Shuyi Li, M.D., Ph.D., Research Scientist, Program in Cancer Biology and Gene Regulation, Institute of Molecular Medicine and Genetics, Medical College of Georgia
We report the development of a therapeutic inhibitor, single chain antibody variable fragment (scFv) against DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in DNA double strand break repair non-homologous end joining pathway. We demonstrate an ability to endow scFv with drug-like properties that allow it to internalize by nondestructive receptor-mediated endocytosis and escape the endocytic compartment to enter the nucleus. The modified scFv inhibited DNA double-strand break repair by binding a regulatory site in DNA-PKcs and sensitized human cancer cells to a clinically relevant dose of ionizing radiation. Results suggest a potentially general approach for targeting intracellular proteins using systemically administered single-chain antibodies.
6:20 Close of Day
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