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.
IDH-305 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HCT116-IDH2R140Q/+ cells
3.8 μM
Weak inhibition of 2-HG production in IDH2 mutant R140Q, IC50 of 3.8 μM
ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121
HCT116-IDH2R172K/+ cells
10 μM
Weak inhibition of 2-HG production in IDH2 mutant R172K, IC50 of 10 μM
ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121
MCF10A-IDH1R132H/+ cells
0.020 μM
Inhibition of EGF-independent proliferation, IC50 of 0.020 μM
ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121
HCT116-IDH1R132H/+ cells
0.024 μM
Inhibition of 2-HG production, IC50 of 0.024 μM
ACS Med Chem Lett. 2017 Sep 18;8(10):1116-1121
Cholangiocarcinoma RBE cell line
5 nM
12 hours
To verify the effect of IDH1 mutation on erastin-induced ferroptosis in cholangiocarcinoma cells, results showed that IDH305 reversed the promoting effect of IDH1 mutation on ferroptosis
Open Med (Wars). 2022 May 6;17(1):863-870
IDH-305 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mouse
HCT116-IDH1R132H/+ xenograft model
Oral
200 mg/kg
Single dose
Inhibition of tumor 2-HG production, maximal inhibition of 87.2%
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