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

Idelalisib (also known as GS-1101, CAL-101, IC489666, and Zydelig) is a PI3K delta 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 PI3K delta. Our data show that idelalisib is a potent and selective inhibitor of the kinase activity of PI3K delta. 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 p110 delta subunit of PI3K delta furthers our understanding of the binding interactions that confer the potency and selectivity of idelalisib.