Identification of novel, selective and potent Chk2 inhibitors.

Abstract A series of isothiazole carboxamidine compounds were synthesized and discovered as novel and selective inhibitors for Chk2. They are not active against the related Chk1 kinase. The structure-activity relationship studies were performed on the scaffold, and enzymatic kinetic analysis showed they are simple ATP competitive inhibitors with K i values as low as 11 nM for Chk2. Computer modeling studies were employed to comprehend the mechanism of action and SAR of these compounds.