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

IDH1 plays 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 IDH1 have 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 IDH1 binding pockets. Importantly, the NADPH competitive
α,β-unsaturated enone 1 makes a unique covalent
linkage through active site H315. As few small molecules have been
shown to covalently react with histidine residues, these data support
the potential utility of an underutilized strategy for reversible
covalent small molecule design.