product name AGI-5198
Description: AGI-5198, also know as IDH-C35, is the first very potent and selective inhibitor of IDH1 R132H/R132C mutants with IC50 of 0.07 μM/0.16 μM. AGI-5198 shows good potency in the U87 R132H cell based assay and ~90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. AGI-5198 induces the expression of genes and cell markers associated with glial-specific differentiation in glioma cell and inhibits tumor growth.
References: Science. 2013 May 3;340(6132):626-30.
462.56
Formula
C27H31FN4O2
CAS No.
1355326-35-0
Storage
-20℃ for 3 years in powder form
-80℃ for 2 years in solvent
Solubility (In vitro)
DMSO: 24 mg/mL (51.9 mM)
Water: <1 mg/mL
Ethanol: 14 mg/mL (30.3 mM)
Solubility (In vivo)
0.5% methylcellulose+0.2% Tween 80: 30mg/mL
Synonyms
IDH-C35
other peoduct :References PubMed ID：:http://www.ncbi.nlm.nih.gov/pubmed/19409898
| In Vitro |
In vitro activity: AGI-5198, potently inhibits mutant IDH1 (R132H-IDH1 and R132C-IDH1), but not wildtype IDH1 (IC50 > 100 μM) or any of IDH2 isoforms (R140Q, R172K, wildtype) (IC50 > 100 μM). AGI-5198, has been shown to have anti-tumor efficacy in the TS603 glioma cell line and to block R-2HG production in a dose-dependent manner. Under conditions of near-complete R-2HG inhibition, AGI-5198 induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant—but not IDH1–wild-type—glioma cells without appreciable changes in genome-wide DNA methylation. Kinase Assay: Compound is prepared as 10 mM stock in DMSO and diluted to 50X final concentration in DMSO, for a 50 μL reaction mixture. IDH enzyme activity converting alpha-ketogluta rate to 2-hydroxyglutarate is measured using a NADPH depletion assay. In the assay the remaining cofactor is measured at the end of the reaction with the addition of a catalytic excess of diaphorase and resazurin, to generate a fluorescent signal in proportion to the amount of NADPH remaining. IDH enzyme activity in the direction of isocitrate to alpha-ketoglutarate conversion is measured by direct coupling of the NADPH production to conversion of resazurin to resorufin by diaphorase. In both cases, resorufin is measured fluorometrically at Ex544 Em 590. Cell Assay: |
|---|---|
| In Vivo | In R132H-IDH1 glioma xenografts, AGI-5198 (450 mg/kg/day) causes 50-60% growth inhibition over a treatment period of three weeks with no affect in the growth of IDH1 wild-type glioma xenografts. Tumors from AGI-5198-treated mice shows reduced staining with an antibody against the Ki-67 protein. But cleaved caspase-3 shows no differences between tumors from vehicle and AGI-5198–treated mice |
| Animal model | IDH1 mutant glioma xenografts |
| Formulation & Dosage | Dissolved in 0.5% MC and 0.2% Tween 80; 150 mg/kg, 450 mg/kg per day; oral gavage |
| References | Science. 2013 May 3;340(6132):626-30. |
