Structural Basis for Isoform Selectivity in a Class of Benzothiazole Inhibitors of Phosphoinositide 3-Kinase γ
Journal of Medicinal Chemistry2014Vol. 58(1), pp. 517–521
Citations Over TimeTop 21% of 2014 papers
Philip N. Collier, Gabriel Martínez-Botella, Mark Cornebise, Kevin M. Cottrell, John Doran, James P. Griffith, Sudipta Mahajan, François Maltais, Cameron Stuver Moody, Emilie Porter Huck, Tiansheng Wang, Alex M. Aronov
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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