| Literature DB >> 30004704 |
Clarissa G Jakob, Anup K Upadhyay, Pamela L Donner, Emily Nicholl, Sadiya N Addo, Wei Qiu, Christopher Ling, Sujatha M Gopalakrishnan, Maricel Torrent, Steven P Cepa, Jason Shanley, Alexander R Shoemaker, Chaohong C Sun, Anil Vasudevan, Kevin R Woller, J Brad Shotwell, Bailin Shaw, Zhiguo Bian, Jessica 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.Entities:
Mesh：
Substances：
Year: 2018 PMID： 30004704 DOI： 10.1021/acs.jmedchem.8b00305
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446