“Fluorescent Probes of Engagement of Drug Targets by Small Molecules in Living Cells”
Blake R. Peterson | Ohio State University
Over 90% of oncology drug candidates that reach clinical trials are not approved by the FDA. One factor that can contribute to these low success rates is a poor understanding of the affinity and selectivity of small molecules for target proteins in physiologically relevant living systems. Although these affinities can often be measured with recombinant proteins, purified proteins do not necessarily faithfully mimic endogenous proteins because biochemical experiments do not precisely replicate the environment within cells. As many as 50% of proteins are post-translationally modified, and endogenous cellular proteins extensively assemble into complexes in specific subcellular environments that affect their functions. To quantify the engagement of intracellular protein targets by small molecules, we are developing fluorescent probe cellular binding assays (FPCBA) that allow studies of native (untagged) full-length proteins in living cells by flow cytometry. These assays use drug-like fluorescent probes to measure interactions of small molecules with specific overexpressed proteins at equilibrium. We are using this approach to investigate the binding of small molecules to multiple drug targets involved in cancer to facilitate drug discovery and development.
Guest Lecturer: Blake R. Peterson, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University
Blake R. Peterson was raised in Reno, Nevada. After receiving a B.S. in Chemistry from the University of Nevada Reno in 1990, he pursued his PhD in Chemistry at UCLA. During this time, he moved with his PhD advisor to Switzerland, where he conducted research for two years at the ETH-Zurich. In 1994, he accepted a postdoctoral position in the Dept. of Chemistry and Chemical Biology at Harvard University as a Damon Runyon / Walter Winchell Cancer Research Foundation Fellow. In 1998, he joined the faculty in the Dept. of Chemistry at Penn State University as an Assistant Professor and was promoted to Associate Professor with tenure in 2004. At Penn State, he was named a research scholar of the American Cancer Society and was the recipient of a Camille Dreyfus Teacher Scholar Award. In 2008, he joined the faculty of the Department of Medicinal Chemistry at the University of Kansas (KU) as Regents Distinguished Professor and Eminent Scholar of the Kansas Biosciences Authority. In 2013, he was elected as a Fellow of the American Association for the Advancement of Science. In 2019, he joined the faculty of The Ohio State University College of Pharmacy as Professor and Chair of the Division of Medicinal Chemistry and Pharmacognosy. He additionally holds appointments at the Ohio State University Comprehensive Cancer Center (OSUCCC) as John W. Wolfe Chair in Cancer Research, Co-Leader of the OSUCCC Translational Therapeutics (TT) Program, and Co-Director of the OSUCCC Medicinal Chemistry Shared Resource (MCSR). As Co-Leader of the TT Program, he oversees basic science efforts and helps faculty initiate small molecule drug discovery projects. As Co-Director of the MCSR, he built and co-leads a new laboratory focused on high-content and high-throughput screening of small molecules against protein targets involved in cancer proliferation. His academic laboratory in the OSU College of Pharmacy uses organic/medicinal chemistry and chemical biology approaches to develop chemical tools for anticancer drug discovery.
Literature reference:
Yin, Y.; Zhao, S. L.; Rane, D.; Lin, Z.; Wu, M.; Peterson, B. R. Quantification of Binding of Small Molecules to Native Proteins Overexpressed in Living Cells. J. Am. Chem. Soc. 2024, 146 (1), 187-200.
