Identification of New Inhibitors of Mutant Isocitrate Dehydrogenase 2 through Molecular Similarity-based Virtual Screening

Background: Isocitrate dehydrogenase 2 (IDH2) is an enzyme catalyzing the oxidative decarboxylation of isocitrate to alpha-ketoglutarate (alpha-KG) in the tricarboxylic acid (TCA). Evidences suggest that the specific mutations in IDH2 are critical to the growth and reproduction of severe tumors especially leukemia and glioblastoma. It is found that the inhibitors of mutant IDH2 are promising anti-tumor therapeutics. Methods: A virtual screening strategy combining molecular similarity search and molecular docking was performed in the binding site of AGI-6780. YL-16, YL-17 and YL-18 were identified as novel mutant IDH2 inhibitors for the reduction of (D)-2-hydroxyglutarate in cellular evaluation. In addition, all the three compounds showed inhibition against IDH2-R172K mutated HEK-293T cells, while weak inhibition against wide-type IDH2 (WT-IDH2) HEK-293T cells. Results: Significantly, YL-17 showed 84.55% inhibitory activity against IDH2-R172K at 1 mu M and weak cytotoxicity to wide-type IDH2 at 50 mu M. Conclusion: YL-17 was highlighted as a new mutant IDH2 inhibitor that could be further developed for therapeutic applications.