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 serves 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 confer on this enzymes a new activity: catalysis of alpha-ketoglutarate (2-OG) to the (R)-enantiomer of 2-hydroxyglutarate (R-2HG).
AG-120 is a selective inhibitor of R132 mutated IDH1. The inhibitory IC50s of AG-120 against IDH1-R132 mutants IDH1-R132H, IDH1-R132C, IDH1-R132G, IDH1-R132L and IDH1-R132S were 12, 13, 8, 13, and 12 nM, respectively. The inhibitory IC50s of AG-120 against IDH1-R132 mutated HT1080, COR-L105 and HCCC-9810 cells were 8, 15 and 12 nM, respectively[2]. In IDH1-R132 mutated samples derived from AML patients, AG-120 reduced the level of intracellular 2-HG by 96% at the lowest tested dose (0.5 μM) and by 98.6% and 99.7%, respectively, at 1 and 5 μM. 5 μM AG-120 also enhanced ability of primary patient myeloblasts to form differentiated colonies in methylcellulose assays[2].
In HT1080 xenografts established in nude mice, a single oral dose of AG-120 at 50 or 150 mg/kg reduced tumor 2-HG concentration with maximum inhibition of 92.0% and 95.2%, respectively, achieved at about 12h post dose[2].
Ivosidenib/艾伏尼布 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Human cholangiocarcinoma cell lines (RBE and SNU1079)
1 μM
To evaluate the effect of AG120 on 5hmC levels and IFN-γ response, results showed AG120 significantly increased 5hmC levels and enhanced IFN-γ response
Cancer Discov. 2022;12(3):812-835.
CKIR132C ICC cells
1 μM
5 days
To assess the effect of AG120 on cell viability, results showed no significant impact on cell viability with AG120 treatment
Cancer Discov. 2022;12(3):812-835.
MOLM14 IDH1 R132H
2 µM
1 week
Evaluate the effect of IDH1 mutant inhibitor on mitochondrial metabolism, results showed maintenance or enhancement of mitochondrial metabolism
J Exp Med. 2021 May 3;218(5):e20200924.
GBC5 PDO
10 µM, 50 µM
96 h
To evaluate the inhibitory effect of Ivosidenib on the growth of GBC5 PDO. Results showed that Ivosidenib did not significantly affect the growth of GBC5 PDO.
Cancer Cell Int. 2021 Oct 2;21(1):519.
THP-1 cells
10 µM
72 h
To study the effect of Ivosidenib on the differentiation of IDH1-mutant AML cells.
Nat Commun. 2022 May 12;13(1):2614.
Ivosidenib/艾伏尼布 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
AML PDX models
Oral gavage
150 mg/kg AG-120, 6 mg/kg IACS-010759
AG-120 twice daily for 3 weeks; IACS-010759 every other day for 3 weeks
Evaluate the anti-leukemic efficacy of IDH1 mutant inhibitor combined with mitochondrial inhibitors, showing significant reduction in tumor burden and enhanced differentiation
J Exp Med. 2021 May 3;218(5):e20200924.
Mice
CKIR132C GEM model and allograft models
Oral
150 mg/kg
Twice daily for 7 days or longer
To evaluate the effect of AG120 on tumor growth and immune microenvironment, results showed AG120 slowed tumor growth, increased CD8+ T cell infiltration and effector function, and restored TET2 activity
Cancer Discov. 2022;12(3):812-835.
Mice
CT26 colorectal carcinoma models and GL261 glioma model
Intravenous
50 mg/kg
Daily for the experimental period
To evaluate the effect of Ivosidenib on alleviating IDH1 mutation-mediated cancer cachexia, results showed that Ivosidenib delayed the progression of cachexia and preserved skeletal muscle mass.
Commun Biol. 2023 Sep 23;6(1):977.
M-NSG mice
Subcutaneous ICC model
Gavage
150 mg/kg
Once every 3 days, for 3 times
To evaluate the inhibitory effect of AdHNF4α and ivosidenib combination therapy on ICC, results showed that the combination therapy significantly suppressed tumor growth
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