Identification and characterization of a novel mutant isocitrate dehydrogenase 1 inhibitor for glioma treatment

Isocitrate dehydrogenase 1 (IDH1) mutant R132H, promoting the oncometabolite D-2-hydroxyglutarate (D2HG), is a driver mutation and an emerging therapeutic target in glioma. This study identified a novel mutant IDH1 inhibitor, WM17, by virtual screening and enzymatic confirmation. It could bind to and increase mutant IDH1 protein's thermostability in both endogenous heterozygous cells and exogenous overexpressed cells. Consequently, WM17 reversed the accumulation of D2HG and histone hypermethylation in IDH1 mutated cells. Finally, we concluded that WM17 significantly inhibited cell migration in IDH1 mutated glioma cells, although it has no apparent effect on cell proliferation. Further studies are guaranteed toward the development of WM17 as a therapeutic agent for IDH1 mutated glioma. (c) 2021 Elsevier Inc. All rights reserved.

Automated summary

A novel mutant IDH1 inhibitor, WM17, was identified in this study, reversing the accumulation of D2HG and histone hypermethylation in IDH1 mutated cells, and significantly inhibiting cell migration.