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Biostructural, biochemical and biophysical studies of mutant IDH1

Author

Listed:
  • Mark A. McCoy

    (Inc.)

  • Jun Lu

    (Inc.)

  • F. Richard Miller

    (Inc.)

  • Stephen M. Soisson

    (Inc.)

  • Michael H. Lam

    (Inc.)

  • Christian Fischer

    (Inc.)

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.

Suggested Citation

  • Mark A. McCoy & Jun Lu & F. Richard Miller & Stephen M. Soisson & Michael H. Lam & Christian Fischer, 2024. "Biostructural, biochemical and biophysical studies of mutant IDH1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51692-0
    DOI: 10.1038/s41467-024-51692-0
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    References listed on IDEAS

    as
    1. Lenny Dang & David W. White & Stefan Gross & Bryson D. Bennett & Mark A. Bittinger & Edward M. Driggers & Valeria R. Fantin & Hyun Gyung Jang & Shengfang Jin & Marie C. Keenan & Kevin M. Marks & Rober, 2009. "Cancer-associated IDH1 mutations produce 2-hydroxyglutarate," Nature, Nature, vol. 462(7274), pages 739-744, December.
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