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    CHIR-124
    CHIR-124

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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 #: V1585
    CAS #: 405168-58-3Purity ≥98%

    Description: CHIR-124 is a novel, potent and selective quinolone-based small molecule Chk1 (Checkpoint kinase1) inhibitor with IC50 of 0.3 nM in a cell-free assay. CHIR-124 is structurally unrelated to other known inhibitors of Chk1. It shows 2,000-fold selectivity against Chk2, 500- to 5,000-fold less activity against CDK2/4 and Cdc2. CHIR-124 interacts synergistically with topoisomerase poisons (e.g., camptothecin and/or SN-38) in causing growth inhibition in several p53-mutant solid tumor cell lines as determined by isobologram or response surface analysis. CHIR-124 is a novel and potent Chk1 inhibitor with promising antitumor activities when used in combination with topoisomerase I poisons. 

    References: Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):591-602; Cell Cycle. 2009 Apr 15;8(8):1196-205.

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    Molecular Weight (MW)419.91
    FormulaC23H22ClN5O 
    CAS No.405168-58-3
    Storage-20℃ for 3 years in powder form
    -80℃ for 2 years in solvent
    Solubility (In vitro)DMSO: 7 mg/mL (16.7 mM)
    Water: <1 mg/mL
    Ethanol: <1 mg/mL
    Solubility (In vivo)1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL 
    SynonymsCHIR124; CHIR-124; CHIR 124


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    In Vitro

    In vitro activity: CHIR-124 is a quinolone-based small molecule that is structurally unrelated to other known inhibitors of Chk1. CHIR-124 interacts synergistically with topoisomerase poisons (e.g., Camptothecin or SN-38) in causing growth inhibition in a variety of cancer cell lines, including breast carcinoma (MDA-MB-231 and MDA-MB-435) and colon carcinoma (SW-620 and Colo205), all of which contains the mutant p53 gene. CHIR-124 abrogates the SN-38-induced S and G2-M checkpoints and potentiates apoptosis in MDA-MD-435 breast cancer cells. The abrogation of the G2-Mcheckpoint and induction of apoptosis by CHIR-124 are enhanced by the loss of p53. CHIR-124 also potently targets other kinases such as PDGFR and Flt3 with IC50 of 6.6 nM and 5.8 nM, respectively.


    Kinase Assay: For the Chk1 assay, the kinase domain is expressed in Sf9 insect cells, and a biotinylated cdc25c peptide containing the consensus Chk1/Chk2 phosphorylation site (*)(biotin-[AHX]SGSGS*GLYRSPSMP-ENLNRPR[CONH2]) is used as the substrate. A dilution series of CHIR-124 is mixed with a kinase reaction buffer containing a final concentration of 30 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 2 mM DTT, 4 mM EDTA, 25 mMβ-glycerophosphate, 5 mM MnCl2, 0.01% bovine serum albumin, 1.35 nM CHK1 kinase domain, 0.5 μM peptide substrate, and 1 AM unlabeled ATP, plus 5 nM 33Pγ-labeled ATP (specific activity = 2,000 Ci/mmol). Reactions and detection of the phosphate transfer are carried out by a radioactive method. Reactions are incubated at room temperature for 1 to 4 hours and the phosphorylated peptide captured on streptavidin-coated microtiter plates containing stop reaction buffer (25 mM EDTA [ethylenediaminetetraacetic acid], 50 mMHEPES, pH 7.5). Phosphorylated peptide is measured with the DELFIA TRF system using a Europium-labeled anti-phosphotyrosine antibody PT66. The concentration of CHIR-124 for IC50 is calculated using nonlinear regression with XL-Fit data analysis software.


    Cell Assay: MDA-MB-231, MDA-MB-435, SW-620, and COLO 205 cells in log-phase are plated into 96-well microplates. CHIR-124 is serially diluted in the presence of six different concentrations of Camptothecin or 0 nM camptothecin. Camptothecin is also serially diluted in the absence of CHIR-124. CHIR-124 is added to cells in 96-well dishes and incubated at 37 °C for 48 hours. Each treatment condition is done in triplicate. Cell proliferation is monitored by the 3-(4,5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS), inner salt assay. MTS inner salt is added to the microplates, which are incubated for another 3 hours, and absorbance at 490 nm is read on a plate reader. The concentrations of each drug in the combinations required to produce 50% inhibition are plotted to generate the isoboles. Isobologram analysis of drug interaction is based the equation of Loewe additivity (1= D A /IC50, A + DB/IC50, B), where IC50, A and IC50, B are the concentrations of drugs to result in 50% inhibition for each drug alone, and DA and DB are concentrations of each drug in the combination that yield 50% overall inhibition. A diagonal line indicating Loewe additivity is included in each graph. Data points that fall below the line indicate synergy, whereas those that fall above the line will indicate antagonism.

    In VivoCHIR-124 potentiates the growth inhibitory effects of Irinotecan by abrogating the G2-M checkpoint and increasing tumor apoptosis in an orthotopic breast cancer xenograft model.
    Animal modelMDA-MB-435 cells are implanted in the mammary fat pad of 8- to 10-week-old female immunodeficient mice.
    Formulation & DosageDissolved in dimethyl sulfoxide and stored in aliquots at -20 °C; 10 mg/kg or 20 mg/kg; oral gavage
    References

    Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):591-602; Cell Cycle. 2009 Apr 15;8(8):1196-205.


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

    CHIR-124

    Synergism between topoisomerase I poisons and CHIR-124 in human cancer cell lines expressing mutant p53.  2007 Jan 15;13(2 Pt 1):591-602.

     

    CHIR-124

    Abrogation of cell cycle checkpoints and induction of apoptosis by CHIR-124 in MDA-MD-435 cells.  2007 Jan 15;13(2 Pt 1):591-602.

     

    CHIR-124

    Suppression of the Chk1 signaling pathway by CHIR-124.  2007 Jan 15;13(2 Pt 1):591-602.


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