Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Surrey, United Kingdom.
Mol Cancer Ther. 2010 Jan;9(1):89-100. doi: 10.1158/1535-7163.MCT-09-0938. Epub 2010 Jan 6.
Genotoxic antitumor agents continue to be the mainstay of current cancer chemotherapy. These drugs cause DNA damage and activate numerous cell cycle checkpoints facilitating DNA repair and the maintenance of genomic integrity. Most human tumors lack functional p53 and consequently have compromised G(1)-S checkpoint control. This has led to the hypothesis that S and G(2)-M checkpoint abrogation may selectively enhance genotoxic cell killing in a p53-deficient background, as normal cells would be rescued at the G(1)-S checkpoint. CHK1 is a serine/threonine kinase associated with DNA damage-linked S and G(2)-M checkpoint control. SAR-020106 is an ATP-competitive, potent, and selective CHK1 inhibitor with an IC(50) of 13.3 nmol/L on the isolated human enzyme. This compound abrogates an etoposide-induced G(2) arrest with an IC(50) of 55 nmol/L in HT29 cells, and significantly enhances the cell killing of gemcitabine and SN38 by 3.0- to 29-fold in several colon tumor lines in vitro and in a p53-dependent fashion. Biomarker studies have shown that SAR-020106 inhibits cytotoxic drug-induced autophosphorylation of CHK1 at S296 and blocks the phosphorylation of CDK1 at Y15 in a dose-dependent fashion both in vitro and in vivo. Cytotoxic drug combinations were associated with increased gammaH2AX and poly ADP ribose polymerase cleavage consistent with the SAR-020106-enhanced DNA damage and tumor cell death. Irinotecan and gemcitabine antitumor activity was enhanced by SAR-020106 in vivo with minimal toxicity. SAR-020106 represents a novel class of CHK1 inhibitors that can enhance antitumor activity with selected anticancer drugs in vivo and may therefore have clinical utility.
遗传毒性抗肿瘤药物仍然是当前癌症化疗的主要手段。这些药物会导致 DNA 损伤，并激活许多细胞周期检查点，促进 DNA 修复和基因组完整性的维持。大多数人类肿瘤缺乏功能性 p53，因此 G(1)-S 检查点控制受损。这导致了这样的假设，即 S 和 G(2)-M 检查点的废除可能会选择性地增强 p53 缺陷背景下的遗传毒性细胞杀伤，因为正常细胞会在 G(1)-S 检查点被挽救。CHK1 是一种与 DNA 损伤相关的丝氨酸/苏氨酸激酶，与 S 和 G(2)-M 检查点控制有关。SAR-020106 是一种 ATP 竞争性、强效且选择性的 CHK1 抑制剂，对分离的人酶的 IC(50)为 13.3 nmol/L。该化合物可废除依托泊苷诱导的 HT29 细胞中的 G(2)期阻滞，IC(50)为 55 nmol/L，并且在体外的几种结肠肿瘤系中和以 p53 依赖的方式显著增强吉西他滨和 SN38 的细胞杀伤作用达 3.0 至 29 倍。生物标志物研究表明，SAR-020106 可抑制细胞毒性药物诱导的 CHK1 在 S296 处的细胞毒性药物诱导的自身磷酸化，并以剂量依赖的方式阻断 CDK1 在 Y15 处的磷酸化，无论是在体外还是体内。细胞毒性药物联合用药与增加的 γH2AX 和多聚 ADP 核糖聚合酶裂解有关，这与 SAR-020106 增强的 DNA 损伤和肿瘤细胞死亡一致。伊立替康和吉西他滨在体内的抗肿瘤活性通过 SAR-020106 增强，而毒性最小。SAR-020106 代表了一类新型的 CHK1 抑制剂，可与选定的抗癌药物在体内增强抗肿瘤活性，因此可能具有临床应用价值。
