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CHIR-124

In stock
Catalog No.
A8394
Chk1 inhibitor,novel and potent
Grouped product items
SizePriceStock Qty
10mM (in 1mL DMSO)
$95.00
In stock
5mg
$88.00
In stock
25mg
$250.00
In stock
50mg
$420.00
In stock

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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

Physical AppearanceA solid
StorageStore at -20°C
M.Wt419.91
Cas No.405168-58-3
FormulaC23H22ClN5O
Solubility≥10.5mg/mL in DMSO
Chemical Name4-[[(3S)-1-azabicyclo[2.2.2]octan-3-yl]amino]-6-chloro-3-(1,3-dihydrobenzimidazol-2-ylidene)quinolin-2-one
SDFDownload SDF
Canonical SMILESC1CN2CCC1C(C2)NC3=C4C=C(C=CC4=NC(=O)C3=C5NC6=CC=CC=C6N5)Cl
Shipping ConditionEvaluation sample solution : ship with blue ice.All other available size: ship with RT , or blue ice upon request
General tipsFor obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.

Biological Activity

Description CHIR-124 is a novel and potent inhibitor of Chk1 with an IC50 value of 0.3 nM.
Targets Chk1 FLT3 PDGFR GSK-3 Fyn  
IC50 0.3 nM 5.8 nM 6.6 nM 23.3 nM 98.8 nM  

Quality Control

Chemical structure

CHIR-124