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:
-
- 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)
- OSTI Identifier:
- 1347695
- Alternate Identifier(s):
- OSTI ID: 1347696
- Grant/Contract Number:
- AC02-05CH11231
- Resource Type:
- Journal Article: 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. https://doi.org/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. 2015.
"Structural, biochemical, and biophysical characterization of idelalisib binding to phosphoinositide 3-kinase δ". United States. https://doi.org/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},
url = {https://www.osti.gov/biblio/1347695},
journal = {Journal of Biological Chemistry},
issn = {0021-9258},
number = 13,
volume = 290,
place = {United States},
year = {Wed Jan 28 00:00:00 EST 2015},
month = {Wed Jan 28 00:00:00 EST 2015}
}
Web of Science
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