Discovery of linear unnatural peptides as potent mutant isocitrate dehydrogenase 1 inhibitors by Ugi reaction

Isocitrate dehydrogenases 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to alpha-ketoglutaric acid (alpha-KG). It is the most frequently mutated metabolic gene in human cancer and its mutations interfere with cell metabolism and epigenetic regulation, thus promoting tumorigenesis. In order to discover potent new mutant IDH1 inhibitors, based on the structure of marketed inhibitor AG-120 (Ivosidenib), we designed, synthesized and evaluated a series of linear unnatural peptide analogues via Ugi reaction, as potential mutant IDH1 inhibitors. All these compounds were evaluated for their inhibition on mutant IDH1 enzyme activity. The structure-activity relationship was discussed on the basis of experimental data, with an attempt to pave the way for future studies. Among them, 43 exhibited potent and selective enzyme inhibitory activity, and showed strong binding affinity with mutant IDH1. It can decrease the cellular concentration of 2-HG, and suppress the proliferation of HT1080 and IDH1 mutant-U-87 cells by selectively inhibiting the activity of mutant IDH1.

Automated summary

Isocitrate dehydrogenases 1 (IDH1) is the most frequently mutated metabolic gene in human cancer, and its mutations interfere with cell metabolism and epigenetic regulation, promoting tumorigenesis. In this study, a series of linear unnatural peptide analogues were designed, synthesized, and evaluated as potential mutant IDH1 inhibitors. Compound 43 showed strong inhibitory activity and binding affinity towards mutant IDH1, and it could effectively decrease the cellular concentration of 2-HG and suppress the proliferation of HT1080 and IDH1 mutant-U-87 cells.