Tse Archie N, Rendahl Katherine G, Sheikh Tahir, Cheema Haider, Aardalen Kim, Embry Millicent, Ma Sylvia, Moler Edward J, Ni Zhi Jie, Lopes de Menezes Daniel E, Hibner Barbara, Gesner Thomas G, Schwartz Gary K
Laboratory of New Drug Development, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Clin Cancer Res. 2007 Jan 15;13(2 Pt 1):591-602. doi: 10.1158/1078-0432.CCR-06-1424.
Chk1 kinase is a critical regulator of both S and G(2)-M phase cell cycle checkpoints in response to DNA damage. This study aimed to evaluate the biochemical, cellular, and antitumor effects of a novel Chk1 inhibitor, CHIR124.
CHIR-124 was evaluated for its ability to abrogate cell cycle checkpoints, to potentiate cytotoxicity, and to inhibit Chk1-mediated signaling induced by topoisomerase I poisons in human tumor cell line and xenograft models.
CHIR-124 is a quinolone-based small molecule that is structurally unrelated to other known inhibitors of Chk1. It potently and selectively inhibits Chk1 in vitro (IC(50) = 0.0003 micromol/L). CHIR-124 interacts synergistically with topoisomerase poisons (e.g., camptothecin or SN-38) in causing growth inhibition in several p53-mutant solid tumor cell lines as determined by isobologram or response surface analysis. CHIR-124 abrogates the SN-38-induced S and G(2)-M checkpoints and potentiates apoptosis in MDA-MD-435 breast cancer cells. The abrogation of the G(2)-M checkpoint and induction of apoptosis by CHIR-124 are enhanced by the loss of p53. We have also shown that CHIR-124 treatment can restore the level of cdc25A protein, which is normally targeted by Chk1 for degradation following DNA damage, indicating that Chk1 signaling is suppressed in the presence of CHIR-124. Finally, in an orthotopic breast cancer xenograft model, CHIR-124 potentiates the growth inhibitory effects of irinotecan by abrogating the G(2)-M checkpoint and increasing tumor apoptosis.
CHIR-124 is a novel and potent Chk1 inhibitor with promising antitumor activities when used in combination with topoisomerase I poisons.
Chk1激酶是响应DNA损伤时S期和G(2)-M期细胞周期检查点的关键调节因子。本研究旨在评估新型Chk1抑制剂CHIR124的生化、细胞及抗肿瘤作用。
在人肿瘤细胞系和异种移植模型中，评估CHIR-124消除细胞周期检查点、增强细胞毒性以及抑制拓扑异构酶I毒物诱导的Chk1介导信号传导的能力。
CHIR-124是一种基于喹诺酮的小分子，其结构与其他已知的Chk1抑制剂无关。它在体外能有效且选择性地抑制Chk1（IC(50)=0.0003微摩尔/升）。通过等效线图或响应面分析确定，CHIR-124与拓扑异构酶毒物（如喜树碱或SN-38）在几种p53突变实体瘤细胞系中协同作用导致生长抑制。CHIR-124消除了SN-38诱导的S期和G(2)-M期检查点，并增强了MDA-MD-435乳腺癌细胞的凋亡。p53缺失增强了CHIR-124对G(2)-M期检查点的消除和凋亡诱导作用。我们还表明，CHIR-124处理可恢复cdc25A蛋白水平，该蛋白在DNA损伤后通常被Chk1靶向降解，这表明在CHIR-124存在时Chk1信号传导被抑制。最后，在原位乳腺癌异种移植模型中，CHIR-124通过消除G(2)-M期检查点和增加肿瘤凋亡来增强伊立替康的生长抑制作用。
CHIR-124是一种新型强效Chk1抑制剂，与拓扑异构酶I毒物联合使用时具有有前景的抗肿瘤活性。
