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AGI-5198

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Chemical Structure| 1355326-35-0 同义名 : IDH-C35
CAS号 : 1355326-35-0
货号 : A276907
分子式 : C27H31FN4O2
纯度 : 99%+
分子量 : 462.559
MDL号 : MFCD24848688
存储条件：

粉末 Sealed in dry,2-8°C

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 20 mg/mL(43.24 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO

DMF: 50 mg/mL(108.09 mM)
动物实验配方：

0.5% methylcellulose+0.2% Tween 80+water 30 mg/mL suspension

生物活性
靶点

  • Dehydrogenase

    R132H-IDH1, IC50:70 nM

    R132C-IDH1, IC50:0.16 μM
描述 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.
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 24900389
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

2.16mL

0.43mL

0.22mL

10.81mL

2.16mL

1.08mL

21.62mL

4.32mL

2.16mL
参考文献

[1]Molenaar RJ, Botman D, et al. Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198. Cancer Res. 2015 Nov 15;75(22):4790-802.

[2]Rohle D, Popovici-Muller J, et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013 May 3;340(6132):626-30.

[3]Rohle D, Popovici-Muller J, Palaskas N, Turcan S, Grommes C, Campos C, Tsoi J, Clark O, Oldrini B, Komisopoulou E, Kunii K, Pedraza A, Schalm S, Silverman L, Miller A, Wang F, Yang H, Chen Y, Kernytsky A, Rosenblum MK, Liu W, Biller SA, Su SM, Brennan CW, Chan TA, Graeber TG, Yen KE, Mellinghoff IK. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science. 2013 May 3;340(6132):626-30. doi: 10.1126/science.1236062. Epub 2013 Apr 4. PMID: 23558169; PMCID: PMC3985613.