2chx

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.

A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling., Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B, Balla T, Weiss WA, Williams RL, Shokat KM, Cell. 2006 May 19;125(4):733-47. Epub 2006 Apr 27. PMID:16647110

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Categories: Homo sapiens | Balla, A. | Balla, T. | Feldman, M E. | Goldenberg, D D. | Gonzalez, B. | Knight, Z A. | Loewith, R. | Shokat, K M. | Stokoe, D. | Toth, B. | Weiss, W A. | Williams, O. | Williams, R L. | Zunder, E R. | 3-kinase | Inhibitor | Kinase | Lipid | Phosphoinositide | Quinazolinone | Signaling | Transferase