Download MendeleyBiostructural, biochemical and biophysical studies of mutant IDH1.
McCoy, M.A., Lu, J., Richard Miller, F., Soisson, S.M., Lam, M.H., Fischer, C.(2024) Nat Commun 15: 7877-7877
- PubMed: 39251618
- DOI: https://doi.org/10.1038/s41467-024-51692-0
- Primary Citation of Related Structures:
8T7D, 8T7N, 8T7O, 9B81 - PubMed 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.
Organizational Affiliation:
MRL, Merck & Co., Inc., Rahway, NJ, USA. mark.mccoy@merck.com.
