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 细胞实验
Cell Line
Concentration
Treated Time
Description
References
SF10602 cells
5 µM
1 week
Inhibition of mIDH1 leads to upregulation of replication-associated pathways and reduction in 2HG levels
Clin Cancer Res. 2023 May 1;29(9):1763-1782.
MGG119 cells
5 µM
1 week
Inhibition of mIDH1 leads to significant reduction in ZMYND8 expression
Clin Cancer Res. 2023 May 1;29(9):1763-1782.
LC1035 cells
5 µM
1 week
Inhibition of mIDH1 leads to significant reduction in ZMYND8 expression
Clin Cancer Res. 2023 May 1;29(9):1763-1782.
TS603 glioma cells
0.07 µM
2 days
AGI-5198 inhibited the ability of the mutant enzyme (mIDH1) to produce R-2HG and inhibited colony formation of TS603 glioma cells in soft agar.
Science. 2013 May 3;340(6132):626-30.
RBE cells
0–40 µM
72 hours
To evaluate the antitumor activity of AGI-5198 on RBE cells, the results showed that AGI-5198 in combination with aloperine had significant synergistic effects.
Int J Mol Sci. 2024 Aug 25;25(17):9226.
HCCC-9810 cells
0–40 µM
72 hours
To evaluate the antitumor activity of AGI-5198 on HCCC-9810 cells, the results showed that AGI-5198 in combination with aloperine had weak synergistic effects.
Int J Mol Sci. 2024 Aug 25;25(17):9226.
IDHmut cells
10 µM
72 hours
Inhibiting 2-HG production restored PC and PE levels to those observed in IDHwt cells.
Cancer Metab. 2018 Apr 3;6:3.
E6E7hTERT cells
1 or 10 µM
72 hours (pre-treatment), 28 days (for colony count)
To assess the effect of AGI-5198 on cell proliferation and clonogenicity. No significant change in clonogenicity was observed except a modest decrease in mutant IDH1 expressing cells only at higher concentrations.
Mol Cancer Res. 2016 Oct;14(10):976-983.
TS676 and TS516 glioma cells
20 µM
AGI-5198 did not affect colony formation of wild-type IDH1 glioma cells.
Science. 2013 May 3;340(6132):626-30.
LC1035
LC1035
To evaluate the effect of AGI-5198 on ZMYND8 protein expression
Clin Cancer Res. 2023 May 1;29(9):1763-1782.
MGG119
MGG119
To evaluate the effect of AGI-5198 on ZMYND8 protein expression
Clin Cancer Res. 2023 May 1;29(9):1763-1782.
SF10602
SF10602
To evaluate changes in transcriptome and epigenome after mIDH1 inhibition
Clin Cancer Res. 2023 May 1;29(9):1763-1782.
AGI-5198 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
Intracranial mIDH1 glioma model
Intraperitoneal injection
10 mg/kg
5 days per week for two weeks
To evaluate the therapeutic efficacy of Pamiparib combined with radiation in mIDH1 glioma
Clin Cancer Res. 2023 May 1;29(9):1763-1782.
Mice
R132H-IDH1 glioma xenografts
Oral
450 mg/kg
Daily treatment for 3 weeks
AGI-5198 significantly inhibited the growth of R132H-IDH1 mutant glioma xenografts but had no effect on wild-type IDH1 glioma.
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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