National Center for
4PS8: Structure Of Pi3k Gamma In Complex With N-[6-(5,6-dimethoxypyridin-3- Yl)-1,3-benzothiazol-2-yl]acetamide
Structural Basis for Isoform Selectivity in a Class of Benzothiazole Inhibitors of Phosphoinositide 3-Kinase gamma
J. Med. Chem. (2015) 58 p.517-521
Phosphoinositide 3-kinase gamma (PI3Kgamma) 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 PI3Kgamma, and achieves its selectivity by exploiting natural sequence differences among PI3K isoforms in this region.