Design Of Selective Pi3k Alpha Inhibitors Starting From A Promiscuous Pan Kinase Scaffold

Starting from compound 1, a potent PI3K alpha inhibitor having poor general kinase selectivity, we used structural data and modelling to identify key exploitable differences between PI3K alpha and the other kinases. This approach led us to design chemical modifications of the central pyrazole, which solved the poor kinase selectivity seen as a strong liability for the initial compound 1. Amongst the modifications explored, a 1,3,4-triazole ring (as in compound 4) as a replacement of the initial pyrazole provided good potency against PI3Ka, with excellent kinase selectivity. (C) 2015 Elsevier Ltd. All rights reserved.