Abstract

Advances in DNA sequencing have greatly increased our understanding of the genetic basis of human disease. However, many of human genes encode proteins that remain uncharacterized and lack selective small-molecule probes. To address these problems, we have introduced activity-based protein profiling (ABPP), a chemical proteomic technology that globally profiles the functional state and small molecule interactions of proteins in native biological systems. In this lecture, I will describe the application of ABPP to generate covalent small molecule interaction (or ligandability) maps of human cells and how this information can guide the discovery of first-in-class chemical probes and drug candidates for disease-relevant proteins. Key themes will include: 1) the importance of assaying proteins in endogenous environments to realize their full small molecule interaction potential; 2) the capacity of covalent chemistry coupled with ABPP to extend the druggability of the proteome to reach historically challenging target families like adaptor/scaffolding proteins and DNA/RNA-binding proteins; and 3) the remarkably diverse ways that allosteric small molecules can regulate protein function in cells.

Biography

Benjamin F. Cravatt

Professor, The Scripps Research Institute

Dr. Cravatt is Professor and Norton B. Gilula Chair of Chemical Biology in the Department of Chemistry at The Scripps Research Institute. His research group is interested in developing chemical proteomic technologies that enable protein and drug discovery on a global scale and applying these methods to characterize biochemical pathways that play important roles in human physiology and disease. Dr. Cravatt obtained his undergraduate education at Stanford University, receiving a B.S. in the Biological Sciences and a B.A. in History. He then received a Ph.D. from The Scripps Research Institute (TSRI) in 1996. Professor Cravatt joined the faculty at TSRI in 1997. Dr. Cravatt is co-founder of several biotechnology companies, including Activx Biosciences, Abide Therapeutics, Vividion Therapeutics, and Belharra Therapeutics. Dr. Cravatt’s honors include the Eli Lilly Award in Biological Chemistry, the ASBMB Merck Award, AACR Award for Achievement in Chemistry in Cancer Research, the Wolf Prize in Chemistry, the Heinrich Wieland Prize, and memberships in the National Academies of Inventors, Medicine, and Sciences.