Kevan M. Shokat
University of California, San Francisco
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Primary Section: 21, Biochemistry Secondary Section: 14, Chemistry Membership Type:
Member
(elected 2009)
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Research Interests
My research focuses on development of chemical tools for the study of protein and lipid kinases in cellular signaling. These enzymes are the central elements in signal transduction pathways which govern all cellular decisions-many cancers are caused by mutations in protein and lipid kinases. We have developed a strategy to selectively perturb any kinase in the genome using a combination of protein engineering and organic synthesis. Using protein engineering to modify the active site of a single kinase, allows differentiation of the kinase of interest from all other kinases. Then, through synthesis of small molecules (substrates or inhibitors) which are incapable of binding to wild-type enzymes, but which specifically bind to the engineered kinase active site, we are able to specifically trace the substrates or functions of over 100 protein kinase in a diverse array of organisms. The term "chemical genetics" has been coined to capture the use of both small molecule chemistry and genetics to specifically target a single enzyme. Recently we have applied the tools of chemical genetics toward understanding growth factor signal transduction including PI3-kinase, Akt, and mTOR regulation in normal and cancer settings. We have uncovered a surprising level of integration within growth factor signaling pathways such as feedback and feedforward loops which either reinforce or counteract the effects of inhibiting single enzymes in the pathway. Our current efforts are to develop chemical ways of short-circuiting such feedback loops to make better drugs to treat cancer.
