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

Jakob, Clarissa G.; Upadhyay, Anup K.; Donner, Pamela L.; Nicholl, Emily; Addo, Sadiya N.; Qiu, Wei; Ling, Christopher; Gopalakrishnan, Sujatha M.; Torrent, Maricel; Cepa, Steven P.; Shanley, Jason; Shoemaker, Alexander R.; Sun, Chaohong C.; Vasudevan, Anil; Woller, Kevin R.; Shotwell, J. Brad; Shaw, Bailin; Bian, Zhiguo; Hutti, Jessica E.

doi:10.1021/acs.jmedchem.8b00305

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

Journal Article · Fri Jul 13 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.8b00305· OSTI ID:1471640

Jakob, Clarissa G. ^[1];

^[1]; Donner, Pamela L. ^[1]; Nicholl, Emily ^[1]; Addo, Sadiya N. ^[1]; Qiu, Wei ^[1]; Ling, Christopher ^[1]; Gopalakrishnan, Sujatha M. ^[1]; Torrent, Maricel ^[1]; Cepa, Steven P. ^[1]; Shanley, Jason ^[1]; Shoemaker, Alexander R. ^[1]; Sun, Chaohong C. ^[1];

^[1]; Woller, Kevin R. ^[1];

^[1]; Shaw, Bailin ^[1]; Bian, Zhiguo ^[1]; Hutti, Jessica E. ^[1]

AbbVie, North Chicago, IL (United States)

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. Furthermore 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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1471640

Journal Information:: Journal of Medicinal Chemistry, Vol. 61, Issue 15; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 20 works

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

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