CHIR-124

SKU: orb1300845

Description

CHIR-124 is a potent and selective inhibitor of Chk1 (IC50: 0.3 nM), exhibiting over 2,000-fold selectivity against Chk2 and minimal activity against Cdc2 and CDK2/4. This small molecule is a valuable research tool for studying DNA damage response pathways in both cellular and animal models of cancer.

Research Area

Cardiovascular Research, Cell Biology, Signal Transduction, Stem Cell & Developmental Biology

Key Properties

• CAS Number: 405168-58-3
• MW: 419.91
• Purity: 98.74% (May vary between batches)
• Formula: C₂₃H₂₂ClN₅O
• SMILES: Clc1ccc2[nH]c(=O)c(-c3nc4ccccc4[nH]3)c(N[C@@H]3CN4CCC3CC4)c2c1
• Target: Src,FLT,GSK-3,Chk,PDGFR,Apoptosis
• Solubility: 10% DMSO+40% PEG300+5% Tween-80+45% Saline:0.5 mg/mL (1.19 mM);Ethanol:< 1 mg/mL (insoluble or slightly soluble);H2O:< 1 mg/mL (insoluble or slightly soluble);DMSO:15 mg/mL (35.72 mM)

Bioactivity

• Target IC50:
  CDK2-CyclinA:0.1911 μM|VEGFR2/Flk1:0.5779 μM|VEGFR1/FLT1:0.4636 μM|bFGFR:2.01 μM|Chk1:0.3 nM|FLT3:5.8 nM|ERK2:4.31 μM|PDGFR:6.6 nM|FGFR3:1.29 μM|CDC2-cyclinB:0.5057 μM|Chk2:697.4 nM|PKCβII:0.58 μM|PKCγ:0.11 μM|PKCα:0.58 μM|PKA:0.1031 μM|CDK4-CyclinD:2.05 μM|PKAbl:2.25 μM|GSK-3:0.0233 μM
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• In Vivo:
  CHIR-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.
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• In Vitro:
  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.
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• Cell Research:
  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(Only for Reference)
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Storage & Handling

• Storage: -20°C
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

Cluster of differentiation antigen 135, CHIR 124, CHIR124, CHIR-124, Chk1, Checkpoint Kinase (Chk), CD135, Apoptosis, inhibit, Fms like tyrosine kinase 3, Fyn, FLT3, GSK3, GSK-3, Inhibitor, PDGFR, Platelet-derived growth factor receptor

Compound Identifiers

PubChem CID

135399748