AGI-5198 is a potent and selective inhibitor of IDH1 R132H and R132C mutants with IC50 values of 0.07 and 0.16 µM, respectively, but not wild-type IDH1, wild-type IDH2, or IDH2 mutants.
Isocitrate dehydrogenases (IDHs) catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. IDH1 is a NADP(+)-dependent isocitrate dehydrogenase found in the cytoplasm and peroxisomes. IDH1 plays a significant role in cytoplasmic NADPH production. Somatic mutations in IDH1 have recently been identified in multiple human cancers. Mutation at the site of R132 of IDH1 confers on this enzyme a new activity: catalysis of alpha-ketoglutarate (2-OG) to the (R)-enantiomer of 2-hydroxyglutarate (R-2HG).
AGI-5198 is a selective inhibitor of R132H or R132C mutated IDH1. The inhibitory IC50s of AGI-5198 against R132H-IDH1 and R132C-IDH1 are 70 nM and 160 nM, respectively. AGI-5198 impaired soft-agar colony formation of glioma TS603 cells bearing R132H-IDH1 at the concentrations of 375 nM and 3000 nM. AGI-5198 suppressed 2-HG production in HT1080 and U87MG cells with IC50 values of 0.48 μM and 0.07 μM, respectively[3].
In R132H-IDH1 bearing TS603 glioma xenografts established in SCID mice, AGI-5198 administrated orally at the dose of 450 mg/kg daily for 3 weeks caused 50-60% tumor growth inhibition, while this same dosing had no affect on the growth of IDH1 wild-type TS516 xenografts[3].
作用机制
AGI-5198 inhibits the IDH1-R132H mutant homodimer.
AGI-5198 细胞研究
细胞系
浓度
检测类型
检测时间
活动说明
数据源
human HT1080 cells
Function assay
48 h
Inhibition of IDH1 R132C mutant overexpressed in human HT1080 cells assessed as inhibition of 2-hydroxyglutarate production after 48 hrs by LC/MS analysis, IC50=0.48 μM
24900389
human U87 cells
Function assay
48 h
Inhibition of IDH1 R132H mutant expressed in human U87 cells assessed as inhibition of 2-hydroxyglutarate production after 48 hrs by LC/MS analysis, IC50=0.07 μM
Inhibition of IDH1 R132C mutant overexpressed in human HT1080 cells assessed as inhibition of 2-hydroxyglutarate production after 48 hrs by LC/MS analysis, IC50=0.48 μM
24900389
human U87 cells
Function assay
48 h
Inhibition of IDH1 R132H mutant expressed in human U87 cells assessed as inhibition of 2-hydroxyglutarate production after 48 hrs by LC/MS analysis, IC50=0.07 μM
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