IHMT-IDH1-053

IHMT-IDH1-053 (compound 16) is an irreversible inhibitor highly selective for the IDH1 R132H mutant, with an IC50 of 4.7 nM. It preferentially targets IDH1 mutants over wild-type IDH1 and IDH2, in both their wild-type and mutant forms. In 293T cells transfected with the IDH1 R132H mutant, IHMT-IDH1-053 reduces 2-hydroxyglutarate (2-HG) production with an IC50 of 28 nM. The compound binds to the R132H protein at an allosteric site near the NADPH binding region, forming a covalent linkage with Cys269. Additionally, IHMT-IDH1-053 inhibits the growth of both the HT1080 cell line and primary acute myeloid leukemia (AML) cells harboring IDH1 R132 mutations [1].