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    AGI-5198
    AGI-5198

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    This product is for research use only, not for human use. We do not sell to patients.
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    InvivoChem Cat #: V0855
    CAS #: 1355326-35-0Purity ≥98%

    Description: AGI-5198 (also know as IDH-C35) is a novel, highly potent and selective inhibitor of IDH1 (isocitrate dehydrogenase 1) R132H/R132C mutants with IC50 of 0.07 μM/0.16 μM and with potential anticancer activity. 

    References: Science. 2013 May 3;340(6132):626-30.

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    Molecular Weight (MW)462.56
    FormulaC27H31FN4O2
    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
    SynonymsIDH C35; AGI5198; IDH-C35;  IDHC35; AGI-5198; AGI 5198; 

    Chemical Name: N-cyclohexyl-2-(N-(3-fluorophenyl)-2-(2-methyl-1H-imidazol-1-yl)acetamido)-2-(o-tolyl)acetamide

    InChi Key: FNYGWXSATBUBER-UHFFFAOYSA-N

    InChi Code: InChI=1S/C27H31FN4O2/c1-19-9-6-7-14-24(19)26(27(34)30-22-11-4-3-5-12-22)32(23-13-8-10-21(28)17-23)25(33)18-31-16-15-29-20(31)2/h6-10,13-17,22,26H,3-5,11-12,18H2,1-2H3,(H,30,34)

    SMILES Code: O=C(NC1CCCCC1)C(N(C2=CC=CC(F)=C2)C(CN3C=CN=C3C)=O)C4=CC=CC=C4C           


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    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: TS603 cells are grown in medium containing either AGI-5198 (1.5μM) or DMSO vehicle control. One week prior to harvest cells are ransferred to differentiation medium (DMEM F12; 15 mM HEPES; 0.06% glucose; B27 without vitamin A; N2; Insulin/transferrin; 1% FBS) containing freshly added retinoic acid (1μM). ChIP of non-crosslinked cells is then carried out using established ChIP methods. 350 μg of lysate is immunoprecipitated-using anti-H3K9Me3, H3K27me3 or Rabbit Control IgG. After washing, ChIP DNA is eluted from protein G beads and analyzed by RT-PCR using SYBR green. Relative occupancy is calculated using the standard curve method and fold enrichment versus IgG. Enrichment in AGI- 5198-treated cells is normalized to vehicle control. Means and standard deviation are calculated from 4 technical replicates.

    In VivoIn 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 modelIDH1 mutant glioma xenografts 
    Formulation & DosageDissolved in  0.5% MC and 0.2% Tween 80; 150 mg/kg, 450 mg/kg per day; oral gavage 
    ReferencesScience. 2013 May 3;340(6132):626-30.


    These protocols are for reference only. InvivoChem does not independently validate these methods.

    AGI-5198

    AGI-5198 impairs growth of IDH1-mutant glioma xenografts in mice. Science. 2013 May 3;340(6132):626-30. 
     
    AGI-5198 promotes astroglial differentiation in R132H-IDH1 mutant cells. Science. 2013 May 3;340(6132):626-30.
     
    Dose-dependent inhibition of histone methylation in IDH1-mutant gliomas after shortterm treatment with AGI-5198. Science. 2013 May 3;340(6132):626-30.
    An R132H-IDH1 inhibitor blocks R-2HG production and soft-agar growth of IDH1-mutant glioma cells. Science.2013 May 3;340(6132):626-30.
     

    AGI-5198

     

    AGI-5198


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