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

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. 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.

Authors:
 [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [1]
  1. Gilead Sciences, Inc., Foster City, CA (United States)
Publication Date:
Research Org.:
Univ. of California, Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1347695
Alternate Identifier(s):
OSTI ID: 1347696
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Journal of Biological Chemistry
Additional Journal Information:
Journal Volume: 290; Journal Issue: 13; Journal ID: ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular Biology
Country of Publication:
United States
Language:
English
Subject:
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

Citation Formats

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, and McGrath, Mary E. Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ. United States: N. p., 2015. Web. doi:10.1074/jbc.m114.634683.
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. Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ. United States. doi:10.1074/jbc.m114.634683.
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, and McGrath, Mary E. Wed . "Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ". United States. doi:10.1074/jbc.m114.634683. https://www.osti.gov/servlets/purl/1347695.
@article{osti_1347695,
title = {Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ},
author = {Somoza, John R. and Koditek, David and Villaseñor, Armando G. and Novikov, Nikolai and Wong, Melanie H. and Liclican, Albert and Xing, Weimei and Lagpacan, Leanna and Wang, Ruth and Schultz, Brian E. and Papalia, Giuseppe A. and Samuel, Dharmaraj and Lad, Latesh and McGrath, Mary E.},
abstractNote = {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.},
doi = {10.1074/jbc.m114.634683},
journal = {Journal of Biological Chemistry},
number = 13,
volume = 290,
place = {United States},
year = {2015},
month = {1}
}

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