Structural basis for isoform selectivity in a class of benzothiazole inhibitors of phosphoinositide 3-kinase γ
Philip N Collier1, Gabriel Martinez-Botella, Mark Cornebise
1Vertex Pharmaceuticals Inc. , 50 Northern Avenue, Boston, Massachusetts 02210, United States.
Abstract:
Phosphoinositide 3-kinase γ (PI3Kγ) is an attractive target to potentially treat a range of disease states. Herein, we describe the evolution of a reported phenylthiazole pan-PI3K inhibitor into a family of potent and selective benzothiazole inhibitors. Using X-ray crystallography, we discovered that compound 22 occupies a previously unreported hydrophobic binding cleft adjacent to the ATP binding site of PI3Kγ, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.
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