Biostructural, biochemical and biophysical studies of mutant IDH1

Mark A. McCoy (), Jun Lu, F. Richard Miller, Stephen M. Soisson, Michael H. Lam and Christian Fischer
Additional contact information
Mark A. McCoy: Inc.
Jun Lu: Inc.
F. Richard Miller: Inc.
Stephen M. Soisson: Inc.
Michael H. Lam: Inc.
Christian Fischer: Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract We report bio-structural, bio-chemical and bio-physical evidence demonstrating how small molecules can bind to both wild-type and mutant IDH1, but only inhibit the enzymatic activity of the mutant isoform. Enabled through x-ray crystallography, we characterized a series of small molecule inhibitors that bound to mutant IDH1 differently than the marketed inhibitor Ivosidenib, for which we have determined the x-ray crystal structure. Across the industry several mutant IDH1 inhibitor chemotypes bind to this allosteric IDH1 pocket and selectively inhibit the mutant enzyme. Detailed characterization by a variety of biophysical techniques and NMR studies led us to propose how compounds binding in the allosteric IDH1 R132H pocket inhibit the production of 2-Hydroxy glutarate.

Date: 2024
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DOI: 10.1038/s41467-024-51692-0

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