| 产品介绍 |
AGI-5198 (IDH-C35) is the first highly potent and selective mutant IDH1 inhibitor that was shown to have anti-tumor efficacy and lower tumor 2HG (2-hydroxyglutarate) in vivo. It inhibits IDH1 R132H mutant and R132C mutant in vitro with IC50 ~0.07 μM and ~0.16 μM, respectively, but not wild-type IDH1 or any of the examined IDH2 isoforms (IC50 > 100 μM). AGI-5198 has good cellular activities in TS603 glioma cell line, also inhibits 2-HG production in HT1080 and U87MG cells with IC50 ~0.48 μM and IC50 ~0.07 μM, respectively. In R132H-IDH1 glioma xenografts (TS603), AGI-5198 (450 mg/kg) caused 50-60% growth inhibition with no signs of toxicity during three weeks of daily treatment, but it did not affect the growth of IDH1 wild-type glioma xenografts (TS516). Under conditions of near complete R-2HG (R-2-hydroxyglutarate) inhibition, AGI-5198 induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mutant IDH1 impaired the growth of IDH1-mutant—but not IDH1-wild-type—glioma cells without appreciable changes in genome-wide DNA methylation. AGI-5198 could serve as a very useful chemical probe to assess the biological consequences of IDH1 mutations and the potential of IDH1 inhibitor for treating IDH1 mutant tumors.
|
