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

Somoza, John R.; Koditek, David; Villaseñor, Armando G.; Novikov, Nikolai; Wong, Melanie H.; Liclican, Albert; Xing, Weimei; Lagpacan, Leanna; Wang, Ruth; Schultz, Brian E.; Papalia, Giuseppe A.; Samuel, Dharmaraj; Lad, Latesh; McGrath, Mary E.

doi:10.1074/jbc.m114.634683

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

Journal Article · Wed Jan 28 00:00:00 EST 2015 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.m114.634683· OSTI ID:1347695

Somoza, John R. ^[1]; Koditek, David ^[1]; Villaseñor, Armando G. ^[1]; Novikov, Nikolai ^[1]; Wong, Melanie H. ^[1]; Liclican, Albert ^[1]; Xing, Weimei ^[1]; Lagpacan, Leanna ^[1]; Wang, Ruth ^[1]; Schultz, Brian E. ^[1]; Papalia, Giuseppe A. ^[1]; Samuel, Dharmaraj ^[1]; Lad, Latesh ^[1]; McGrath, Mary E. ^[1]

Gilead Sciences, Inc., Foster City, CA (United States)

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. Here, 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. Lastly, 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.

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Research Organization:: Univ. of California, Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1347695

Alternate ID(s):: OSTI ID: 1347696

Journal Information:: Journal of Biological Chemistry, Vol. 290, Issue 13; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 112 works

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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
CAL-101
enzyme kinetics
enzyme mechanism
enzyme purification
GS-1101
PI3K
PI3Kδ
phosphatidylinositide 3-kinase (PI 3-kinase)
surface plasmon resonance (SPR)
zydelig

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

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