Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315.

IDH1plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1binding pockets. Importantly, the NADPH competitive α,β-unsaturated enone1 makes a unique covalent linkage through active site H315. As few small moleculeshave been shown to covalently react with histidine residues, these data support the potential utility of an underutilized strategy for reversible covalent small moleculedesign.