A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling |
| |
Authors: | Knight Zachary A Gonzalez Beatriz Feldman Morri E Zunder Eli R Goldenberg David D Williams Olusegun Loewith Robbie Stokoe David Balla Andras Toth Balazs Balla Tamas Weiss William A Williams Roger L Shokat Kevan M |
| |
Institution: | Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA. |
| |
Abstract: | Phosphoinositide 3-kinases (PI3-Ks) are an important emerging class of drug targets, but the unique roles of PI3-K isoforms remain poorly defined. We describe here an approach to pharmacologically interrogate the PI3-K family. A chemically diverse panel of PI3-K inhibitors was synthesized, and their target selectivity was biochemically enumerated, revealing cryptic homologies across targets and chemotypes. Crystal structures of three inhibitors bound to p110gamma identify a conformationally mobile region that is uniquely exploited by selective compounds. This chemical array was then used to define the PI3-K isoforms required for insulin signaling. We find that p110alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110beta is dispensable but sets a phenotypic threshold for p110alpha activity. Compounds targeting p110alpha block the acute effects of insulin treatment in vivo, whereas a p110beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|