CHIR-124

405168-58-3

C23H22ClN5O

DMSO : 14 mg/mL (33.34 mM; Need ultrasonic and warming)

Protein Tyrosine Kinase/RTK; Protein Tyrosine Kinase/RTK; Cell Cycle/DNA Damage

CHIR-124 is a potent and selective Chk1 inhibitor with IC₅₀ of 0.3 nM, and also potently targets PDGFR and FLT3 with IC₅₀s of 6.6 nM and 5.8 nM. IC50 & Target: IC50: 0.3 nM (Chk1), 5.8 nM (FLT3), 6.6 nM (PDGFR)^[1] In Vitro: CHIR-124 is 500- to 5, 000-fold less active against other cell cycle kinases, such as cyclin-dependent kinase 2/cyclin A (0.19 uM), cdc2/cyclin B (0.51 uM), and cyclin-dependent kinase 4/cyclin D (2.1 uM). CHIR-124 (>=0.9 nM) in combination with SN-38 (>=0.42 nM) causes significant synergy or >10% deviation from additivity in human cancer cell lines expressing mutant p53, and these values overlap and fall below the IC₅₀s for SN-38 (1.2x10^-7 M) and CHIR-124 (2.2x10^-7 M), respectively. Moreover, CHIR-124 (100 nM) abrogates the SN-38-induced S and G2-M phase cell cycle checkpoints. CHIR-124 (200 nM) leads to a 2.5-fold elevated level of cdc25A above that of the untreated HCT116 p53^?/? cells. The down-regulation of cdc25A induced by SN-38 is completely restored by concurrent or sequential treatment with CHIR-124, proving that CHIR-124 inhibits the Chk1-mediated destruction of cdc25A in whole cells^[1]. CHIR-124 occupies the ATP-binding site, inhibits Chk1 (IC₅₀, 0.3 nM) 2, 000-fold more potently than Chk2 (IC₅₀, 0.7 uM)^[2]. In Vivo: CHIR-124 (10 or 20 mg/kg, p.o.) does not have a significant effect on tumor growth when compared with the vehicle-treated group, but it potentiates the growth inhibitory effect of CPT-11 in a human breast carcinoma xenograft model. The potentiation of the tumor growth inhibitory effect of CPT-11 by CHIR-124 is associated with an increase in apoptosis induction in the tumors. CHIR-124 reverses the suppression of phospho-H3 staining induced by CPT-11, indicating abrogation of the G2-M checkpoint by CHIR-124^[1].