Identification of new IDH2R140Q inhibitors by discriminatory analysis‐based molecular docking and biological evaluation
Xiaoyun Chen, Xianmin Wu, Jian Gao, Huazhou Ying, Xiaowu Dong, Jinxin Che, Zhijian Shen · Archiv der Pharmazie · 2020
Abstract Isocitrate dehydrogenase 2 (IDH2) is a key enzyme in the regulation of cell metabolism. Its mutated type can lead to the accumulation of 2‐hydroxyglutarate, which is often related to malignancies such as acute myeloid leukemia. Therefore, it is necessary to find new inhibitors targeting mutant IDH2. Discriminatory analysis‐based molecular docking was employed to screen the ChemDiv compound library, which resulted in the identification of three new IDH2R140Q inhibitors with moderate‐to‐good IC50 values. Among them, compounds 1 and 3 displayed good selectivity against other mutant or wild‐type IDH proteins. The most potent compound 1, bearing the [1,2,4]triazolo[1,5‐a]pyrimidin scaffold, was subjected to dynamic simulations to provide more information on the binding mode with IDH2R140Q, providing structural clues to further optimize compound 1 as a new mutant IDH2 inhibitor.