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.

我们报告了生物结构、生物化学和生物物理证据，证明了小分子如何与野生型和突变型 IDH1 结合，但仅抑制突变亚型的酶活性。通过 X 射线晶体学，我们表征了一系列与突变体 IDH1 结合的小分子抑制剂，这些抑制剂与市售的抑制剂 Ivosidenib 不同，我们已经确定了 X 射线晶体结构。在整个行业中，几种突变的 IDH1 抑制剂化学型与该变构 IDH1 口袋结合并选择性抑制突变酶。通过各种生物物理技术和 NMR 研究进行的详细表征，我们提出了在变构 IDH1 R132H 口袋中结合的化合物如何抑制 2-羟基戊二酸的产生。