[HTML][HTML] A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling

ZA Knight, B Gonzalez, ME Feldman, ER Zunder… - Cell, 2006 - cell.com
ZA Knight, B Gonzalez, ME Feldman, ER Zunder, DD Goldenberg, O Williams, R Loewith
Cell, 2006cell.com
Summary 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 p110γ identify a conformationally mobile region that is uniquely exploited …
Summary
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 p110γ 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 p110α is the primary insulin-responsive PI3-K in cultured cells, whereas p110β is dispensable but sets a phenotypic threshold for p110α activity. Compounds targeting p110α block the acute effects of insulin treatment in vivo, whereas a p110β inhibitor has no effect. These results illustrate systematic target validation using a matrix of inhibitors that span a protein family.
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