Structural, Biochemical, and Biophysical Characterization of Idelalisib Binding to Phosphoinositide 3-Kinase δ

• Published in: The Journal of biological chemistry Vol. 290; no. 13; pp. 8439 - 8446
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.03.2015; American Society for Biochemistry and Molecular Biology
• Subjects: Adenosine Triphosphate - chemistry; Androstadienes - chemistry; Animals; BASIC BIOLOGICAL SCIENCES; Binding, Competitive; CAL-101; Catalytic Domain; Class I Phosphatidylinositol 3-Kinases; Class Ia Phosphatidylinositol 3-Kinase - chemistry; Crystallography, X-Ray; Enzyme Kinetics; Enzyme Mechanism; Enzyme Purification; GS-1101; Humans; Hydrogen Bonding; INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Kinetics; Mice; Models, Molecular; Phosphatidylinositide 3-Kinase (PI 3-Kinase); Phosphatidylinositol 3-Kinases - chemistry; Phosphoinositide-3 Kinase Inhibitors; PI3K; PI3Kδ; Protein Binding; Protein Structure and Folding; Purines - chemistry; Quinazolinones - chemistry; Surface Plasmon Resonance (SPR); Wortmannin; Zydelig; Enzyme Purification; Zydelig; Surface Plasmon Resonance (SPR); CAL-101; PI3K; Enzyme Mechanism; Phosphatidylinositide 3-Kinase (PI 3-Kinase); PI3Kδ; Enzyme Kinetics; GS-1101
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.634683

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. Background: Idelalisib is a PI3Kδ inhibitor used to treat hematological malignancies. Results: Idelalisib is selective, noncovalent, reversible, and ATP-competitive. Conclusion: The crystal structure helps explain the potency and selectivity of idelalisib. The biophysical and biochemical data clarify the details of the inhibitor's interactions with PI3Kδ. Significance: Its use in humans makes it important to understand how idelalisib inhibits PI3Kδ.