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

J Med Chem. 2018 Aug 9;61(15):6647-6657. doi: 10.1021/acs.jmedchem.8b00305. Epub 2018 Jul 30.

Abstract

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.

MeSH terms

  • Cell Line, Tumor
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Histidine*
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / chemistry*
  • Isocitrate Dehydrogenase / genetics
  • Isocitrate Dehydrogenase / metabolism
  • Ligands
  • Molecular Docking Simulation
  • Mutation
  • Protein Conformation
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Ligands
  • Histidine
  • Isocitrate Dehydrogenase
  • IDH1 protein, human