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CHIR-124

Catalog No.GC15739

CHIR-124 est un inhibiteur puissant et sélectif de Chk1 avec une IC50 de 0,3 nM, et cible également puissamment PDGFR et FLT3 avec des IC50 de 6,6 nM et 5,8 nM.

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CHIR-124 Chemical Structure

Cas No.: 405168-58-3

Taille Prix Stock Qté
10mM (in 1mL DMSO)
70,00 $US
En stock
5mg
66,00 $US
En stock
25mg
176,00 $US
En stock
50mg
319,00 $US
En stock

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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Protocol

Kinase experiment:

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 mM β-glycerophosphate, 5 mM MnCl2, 0.01% bovine serum albumin, 1.35 nM CHK1 kinase domain, 0.5 μM peptide substrate, and 1 μM unlabeled ATP, plus 5 nM 33P γ-labeled ATP (specific activity =2,000 Ci/mmol). Reactions and detection of the phosphate transfer are carried out by a radioactive method.

Animal experiment:

Severe combined immunodeficient mice harboring MDA-MD-435 tumor xenografts are randomized into the following treatment groups of 10: vehicle (captisol) alone, 5 mg/kg CPT-11, 10 mg/kg CHIR-124, 20 mg/kg CHIR-124, 5 mg/kg CPT-11 plus 10 mg/kg CHIR-124, or 5 mg/kg CPT-11 plus 20 mg/kg CHIR-124. Treatment is initiated on the day after randomization (day 1). CPT-11 is given i.p. daily (four times daily) ×5 on days 1 to 5, whereas CHIR-124 is given orally four times daily ×6 on days 2 to 7 in captisol. Percent tumor growth inhibition is defined as % T/C, where T = the treatment group mean, and C = the control group mean. In a similar study, tumors harvested from mice sacrificed on day 4 of treatment are examined for apoptosis by terminal deoxynucleotidyl transferase-mediated nick-end labeling staining and for mitotic index by immunofluorescence labeling with phospho-histone H3 antibody.

References:

[1]. Tse AN, et al. CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo. Clin Cancer Res, 2007, 13(2 Pt 1), 591-602.
[2]. Dai Y, et al. New insights into checkpoint kinase 1 in the DNA damage response signaling network. Clin Cancer Res, 2010, 16(2), 376-383.

Background

CHIR-124, a selective inhibitor, inhibits Chk1 with IC50 value of 0.3nM 2,000-fold more potently than Chk2 with IC50 value of 0.7μM. CHIR-124 also potently targets other kinases such as PDGFR with IC50 value of 6.6nM and FLT3 with IC50 value of 5.8nM [1].

CHIR-124 abrogates the S and G2-M checkpoints induced by topoisomerase I poisons and selectively sensitizes tumors lacking p53 function to undergo mitotic death. In addition, CHIR-124 enhances the antitumor effect of irinotecan in tumor xenografts by inhibiting the G2-M checkpoint and inducing apoptosis.

In vitro, the effect of a matrix of camptothecin and CHIR-124 combinations in a number of human cancer cell lines, including breast carcinoma (MDA-MB-231and MDAMB-435) and colon carcinoma (SW-620 and Colo205), all of which are mutant for p53. When cells were simultaneously exposed to a matrix of different concentration combinations of CHIR-124 and SN-38 for 48 h, significant synergy or >10% deviation from additivity was observed in the concentration ranges of ≥4.2×108 mol/L for SN-38 and≥ 6.0×108 mol/L for CHIR-124. Compared to IR alone, the number of mitotic cells increased dramatically in p53-/- HCT116 cells after concomitant Chir-124 exposure, while no such effect was observed in p53-sufficient WT HCT116 cells. Chir-124 was able to radiosensitize HCT116 cells that lack checkpoint kinase-2 (CHK2) or that were deficient for the spindle checkpoint protein Mad2. Additionally, Chir-124 could radiosensitize tetraploid cell lines, which were resistant to DNA damaging agents. Radiosensitization mediated by Chir-124 is greatly influenced by the p53 and cell cycle checkpoint system [1, 2].

In vivo, severe combined immunodeficient mice harboring MDA-MD-435 tumor xenografts were randomized into the treatment of 10 mg/kg CHIR-124, 20 mg/kg CHIR-124, 10 mg/kg CHIR-124 with 5 mg/kg CPT-11, or 20 mg/kg CHIR-124 with 5 mg/kg CPT-11. CPT-11 was given i.p. four times daily ×5 on days 1 to 5, while CHIR-124 was given orally four times daily ×6 on days 2 to 7 in captisol. Tumors harvested from mice sacrificed on day 4 of treatment were examined for apoptosis by terminal deoxynucleotidyl transferase-mediated nick-end labeling staining and for mitotic index by immunofluorescence labeling with phospho-histone H3 antibody in a similar study [1].

References:
[1]. Tse AN, Rendahl KG, Sheikh T, et al. CHIR-124, a novel potent inhibitor of Chk1, potentiates the cytotoxicity of topoisomerase I poisons in vitro and in vivo. Clinical Cancer Research, 2007, 13(2): 591-602.
[2]. Tao YG, Leteur C, Yang CY, et al. Radiosensitization by Chir-124, a selective CHK1 inhibitor Effects of p53 and cell cycle checkpoints. Cell Cycle, 2007, 8(8): 1196-1205.

Chemical Properties

Cas No. 405168-58-3 SDF
Chemical Name 4-[[(3S)-1-azabicyclo[2.2.2]octan-3-yl]amino]-6-chloro-3-(1,3-dihydrobenzimidazol-2-ylidene)quinolin-2-one
Canonical SMILES C1CN2CCC1C(C2)NC3=C4C=C(C=CC4=NC(=O)C3=C5NC6=CC=CC=C6N5)Cl
Formula C23H22ClN5O M.Wt 419.91
Solubility ≥ 10.5mg/mL in DMSO Storage Store at -20°C
General tips Please select the appropriate solvent to prepare the stock solution according to the solubility of the product in different solvents; once the solution is prepared, please store it in separate packages to avoid product failure caused by repeated freezing and thawing.Storage method and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored at -20°C, please use it within 1 month.
To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time.
Shipping Condition Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request.

Complete Stock Solution Preparation Table

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1 mg 5 mg 10 mg
1 mM 2.3815 mL 11.9073 mL 23.8146 mL
5 mM 0.4763 mL 2.3815 mL 4.7629 mL
10 mM 0.2381 mL 1.1907 mL 2.3815 mL
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Average Rating: 5 ★★★★★ (Based on Reviews and 13 reference(s) in Google Scholar.)

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