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A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.

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.

journal_name

Cell

journal_title

Cell

authors

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

doi

10.1016/j.cell.2006.03.035

subject

Has Abstract

pub_date

2006-05-19 00:00:00

pages

733-47

issue

4

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(06)00498-3

journal_volume

125

pub_type

杂志文章

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