Checkpoint kinase 1 (Chk1) regulates S and G2-M phase cell cycle checkpoints in response to DNA damage. CHIR124 is a cell-permeable, quinolone-based inhibitor of Chk1 (IC50 = 0.3 nM in vitro). It demonstrates high selectivity for Chk1 by displaying inhibitory values 2,000-fold higher against Chk2 (IC50 = 0.7 μM). In synergy with topoisomerase I poisons or ionizing radiation, CHIR124 can inhibit the growth of p53-mutant solid tumor cells both in vitro and in a xenograft model, potentiating tumor apoptosis.
CHIR 124 is a cell-permeable molecule with a quinolone-based structure. It inhibits checkpoint kinase 1 (Chk1) which regulates S and G2-M cekk cycle checkpoints in response to DNA damage. Application towards inhibition of tumor cell growth.
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].
Chk1: 0.3 nM (IC50); Chk2: 697.4 nM (IC50); PDGFR: 6.6 nM (IC50); FLT3: 5.8 nM (IC50); Cdk4/cyclin D: 2.05 μM (IC50); CDC2/cyclin B: 0.5057 μM (IC50); Cdk2/cyclin A: 0.1911 μM (IC50); bFGFR: 2.01 μM (IC50); FGFR3: 1.29 μM (IC50); VEGFR2 FLK1: 0.5779 μM (IC50); VEGFR1 FLT1: 0.4636 μM (IC50); PKCα: 0.58 μM (IC50); PKAβ I: 2.25 μM (IC50); PKCβ II: 0.58 μM (IC50); PKCγ: 0.11 μM (IC50); ERK2: 4.31 μM (IC50); PKA: 0.1031 μM (IC50); GSK3: 0.0233 μM (IC50)
[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.
