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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 2?HG (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.

How to Use:

In vitro:? AGI-5198 was suggested to be used at 1.5-10μM final concentration in vitro.

In vivo: AGI-5198 could be orally dosed to mice at 150-450 mg/kg once per day for up to 3 weeks in glioma xenografts. ?It could be intraperitoneally (IP) dosed to mice at 50-150 mg/kg once or twice per day (formulation: 0.5% MC and 0.2% Tween 80) in the other animal studies.

Reference:

1. 1. Dan Rohle, et al. An Inhibitor of Mutant IDH1 Delays Growth and Promotes Differentiation of Glioma Cells. (2013) Science.340(6132):626-30.?
2. 2. Janeta Popovici-Muller, et al. Discovery of the First Potent Inhibitors of Mutant IDH1 That Lower Tumor 2-HG in Vivo. (2012) ACS Med. Chem. Lett. 3 (10), pp 850–855
3. 3. Lenny Dang, et al.? Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. (2009) Nature 462, 739-744.
4. 4. Turcan S, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. (2012) Nature. 483(7390):479-83.
5. 5. Popovicimuller Janeta, et al. THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHOD OF USE. (2012) PCT WO 2012009678.?

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