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

Journal of Medicinal Chemistry
Clarissa G JakobJessica E Hutti

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.

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Citations

Nov 27, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Viviana CuartasMaría-Jesús Pérez-Pérez
Jun 23, 2020·Expert Opinion on Therapeutic Patents·Jacob E MooseJames L Hougland
May 21, 2020·Journal of Medicinal Chemistry·Matthew D Lloyd
Apr 10, 2021·Cold Spring Harbor Molecular Case Studies·Zoltán N OltvaiPawel Mroz
Nov 15, 2019·Journal of Medicinal Chemistry·Jonathan PettingerMatthew D Cheeseman

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