Isocitrate dehydrogenase 1 (IDH1) is a NADP+ , metal dependent oxidoreductase and wild-type IDH1 catalyzes the oxidative decarboxylation of isocitrate to give α-ketoglutarate (α-KG), while NADP+ is converted to NADPH. Mutations in IDH1 at Arg132 have been tightly associated to various cancers, including glioma, glioblastoma, AML, chondrosarcoma, and cholangiocarcinoma[2]. IDH-305 is a potent and selective inhibitor of IDH1 R132H and R132C with IC50 of 27 and 28 nM, respectively. HCT116-IDH1R132H+/- mechanistic xenograft model treated with a single oral dose of 200 mg/kg IDH-305 showed reduction of tumor 2-HG concentration with maximal 2-HG inhibition of 87.2 ± 1.5% relative to the vehicle treated tumors 8 h post treatment[2].
作用机制
IDH-305 demonstrated a hydrophobic collapse conformation. The aminopyrimidine moiety forms a pair of hydrogen bonds with the backbone atoms of Ile128, while the carbonyl of the oxazolidinone forms a hydrogen bond with the backbone amide of Leu120, and the alpha-methyl fits into the methyl nook.
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