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, and Jessica E. Hutti
J. Med. Chem, 2018 61 (15), 6647–6657
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.
A blog highlighting recent publications in the area of covalent modification of proteins, particularly relating to covalent-modifier drugs. @CovalentMod on Twitter, @covalentmod@mstdn.science on Mastodon, and @covalentmod.bsky.social on BlueSky
Redirecting the pioneering function of FOXA1 with covalent small molecules
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