AGI-5198 (also know as IDH-C35) is a potent and selective mutant IDH1 inhibitor. AGI-5198 has been shown to have anti-tumor efficacy in the TS603 glioma cell line and to lower tumor 2-HG production in HT1080 and U87MG cells with IC50 values of 0.48 μM and 0.07 μM, respectively. AGI-5198 (IDH-C35) inhibits IDH1 R132H mutant and R132C mutant in vitro with IC50 of 0.07 μM and 0.16 μM respectively, but not wild-type IDH1 or any of the examined IDH2 isoforms (IC50 > 100 μM). In R132H-IDH1 glioma xenografts, AGI-5198 (450 mg/kg/day) caused 50-60% growth inhibition over a treatment period of three weeks with no affect in the growth of IDH1 wild-type glioma xenografts. Under conditions of near complete 2-HG inhibition, AGI-5198 can induce demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation.
|Source||Cancer Res (2015). Figure 1. AGI-5198|
|Cell Lines||IDH1MT cells|
|Incubation Time||72 h|
|Results||After 72 hours of incubation in the presence of AGI-5198, IDH-mediated NADPH production capacity of lDH1WT/R132H HCT116 cells was restored to levels comparable with those of lDH1WT/WT HCT116 cells|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.
Rohle D, et al. Science. 2013 May 3;340(6132):626-30. PMID: 23558169.
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