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. 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.
authors: From the Departments of Structural Chemistry and john.somoza@gilead.com.
authors: John R
authors: JR
authors: Somoza
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: David
authors: D
authors: Koditek
authors: From the Departments of Structural Chemistry and.
authors: Armando G
authors: AG
authors: Villaseñor
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Nikolai
authors: N
authors: Novikov
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Melanie H
authors: MH
authors: Wong
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Albert
authors: A
authors: Liclican
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Weimei
authors: W
authors: Xing
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Leanna
authors: L
authors: Lagpacan
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Ruth
authors: R
authors: Wang
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Brian E
authors: BE
authors: Schultz
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Giuseppe A
authors: GA
authors: Papalia
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Dharmaraj
authors: D
authors: Samuel
authors: Biology, Gilead Sciences, Inc., Foster City, California 94404.
authors: Latesh
authors: L
authors: Lad
authors: From the Departments of Structural Chemistry and.
authors: Mary E
authors: ME
authors: McGrath
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000730:Androstadienes / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D020134:Catalytic Domain; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000737:chemistry; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding; D011687:Purines / Q000737:chemistry*; D052999:Quinazolinones / Q000737:chemistry*; D000077191:Wortmannin
chemical_list: D000255:Adenosine Triphosphate; D000730:Androstadienes; D058534:Class I Phosphatidylinositol 3-Kinases; D058543:Class Ia Phosphatidylinositol 3-Kinase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; D000077191:Wortmannin; C421683:Pik3cd protein, mouse; C552946: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
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