IDH (Isocitrate dehydrogenase) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle. Recurrent mutations in IDH1 or IDH2 are prevalent in several cancers including glioma, acute myeloid leukemia (AML), cholangiocarcinoma and chondrosarcoma. Vorasidenib is a pan-IDH inhibitor with IC50 values of 31.9nM and 31.7nM for IDH1-R132H and IDH2-R140Q, respectively[6], which fully penetrates the blood-brain barrier and selectively inhibits mutant IDH protein and induce cell differentiation in in vitro and in vivo models[7]. It is a rapid-equilibrium inhibitor of mIDH1-R132H and mIDH2-R172K homodimer enzymes and is a slow-binding inhibitor of mIDH2-R140Q homodimer and wild type (wt) IDH1/mIDH1-R132H, wtIDH2/mIDH2-R140Q, and wtIDH2/mIDH2-R172K heterodimers. The IC50 range for 2-HG inhibition by AG-881 was 0.04-22 nM in cells expressing mIDH1-R132C, mIDH1-R132G, mIDH1-R132H, or mIDH1-R132S mutations and was 7-14nM and 130nM in cells expressing mIDH2-R140Q and mIDH2-R172K mutations, respectively. The treatment of these mIDH cell lines or primary human acute myeloid leukemia samples with AG-881 led to the onset of cellular differentiation[3]. It has been developed and is in early phase I testing for patients with IDH mutation-positive hematologic malignancies and solid tumors, including glioma[8].
作用机制
AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets. It allosterically inhibits IDH activity by incurring steric hindrance.[6]
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