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J Biol Chem. 2015 Mar 27;290(13):8439-46. doi: 10.1074/jbc.M114.634683. Epub 2015 Jan 28.

Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ.

Author information

1
From the Departments of Structural Chemistry and john.somoza@gilead.com.
2
Biology, Gilead Sciences, Inc., Foster City, California 94404.
3
From the Departments of Structural Chemistry and.

Abstract

Idelalisib (also known as GS-1101, CAL-101, IC489666, and Zydelig) is a PI3Kδ inhibitor that has recently been approved for the treatment of several hematological malignancies. Given its use in human diseases, we needed a clear picture of how idelalisib binds to and inhibits PI3Kδ. Our data show that idelalisib is a potent and selective inhibitor of the kinase activity of PI3Kδ. A kinetic characterization clearly demonstrated ATP-competitive inhibition, and several additional biochemical and biophysical assays showed that the compound binds reversibly and noncovalently to the kinase. A crystal structure of idelalisib bound to the p110δ subunit of PI3Kδ furthers our understanding of the binding interactions that confer the potency and selectivity of idelalisib.

KEYWORDS:

CAL-101; Enzyme Kinetics; Enzyme Mechanism; Enzyme Purification; GS-1101; PI3K; PI3Kδ; Phosphatidylinositide 3-Kinase (PI 3-Kinase); Surface Plasmon Resonance (SPR); Zydelig

PMID:
25631052
PMCID:
PMC4375495
DOI:
10.1074/jbc.M114.634683
[Indexed for MEDLINE]
Free PMC Article

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