A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling

Zachary A. Knight, Beatriz Gonzalez, Morri E. Feldman, Eli R. Zunder, David D. Goldenberg, Olusegun Williams, Robbie Loewith, David Stokoe, Andras Balla, Balazs Toth, Tamas Balla, William A. Weiss, Roger L. Williams, Kevan M. Shokat

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860 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)733-747
Number of pages15
Issue number4
Publication statusPublished - May 19 2006


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Knight, Z. A., Gonzalez, B., Feldman, M. E., Zunder, E. R., Goldenberg, D. D., Williams, O., Loewith, R., Stokoe, D., Balla, A., Toth, B., Balla, T., Weiss, W. A., Williams, R. L., & Shokat, K. M. (2006). A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling. Cell, 125(4), 733-747. https://doi.org/10.1016/j.cell.2006.03.035