期刊
CELL
卷 127, 期 3, 页码 27-41出版社
CELL PRESS
DOI: 10.1016/j.cell.2006.03.035
关键词
-
资金
- MRC [MC_U105184308] Funding Source: UKRI
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 p110 gamma 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 p110 alpha is the primary insulin-responsive PI3-K in cultured cells, whereas p110 beta is dispensable but sets a phenotypic threshold for p110 alpha activity. Compounds targeting p110 alpha block the acute effects of insulin treatment in vivo, whereas a p110 beta inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.
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