Ashwell Susan, Janetka James W, Zabludoff Sonya
AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
Expert Opin Investig Drugs. 2008 Sep;17(9):1331-40. doi: 10.1517/13543784.17.9.1331.
Checkpoint kinase 1 (Chk1), a serine/threonine kinase, functions as a regulatory kinase in cell cycle progression and is a critical effector of the DNA-damage response. Inhibitors of Chk1 are known to sensitise tumours to a variety of DNA-damaging agents and increase efficacy in preclinical models.
The most advanced agents are now in Phase I clinical trials; the preclinical profiles of these drugs are compared and contrasted, together with a discussion of some of the opportunities and challenges facing this potentially revolutionary approach to cancer therapy.
A review of the publications and presentations on XL-844, AZD7762 and PF-477736.
RESULTS/CONCLUSIONS: Chk kinases are part of the DNA damage recognition and response pathways and as such represent attractive targets. Agents that target checkpoint kinases have demonstrated impressive evidence preclinically that this approach will provide tumour-specific potentiating agents and may have broad therapeutic utility.
关卡激酶1（Chk1）是一种丝氨酸/苏氨酸激酶，在细胞周期进程中作为调节激酶发挥作用，是DNA损伤反应的关键效应器。已知Chk1抑制剂可使肿瘤对多种DNA损伤剂敏感，并在临床前模型中提高疗效。
目前最先进的药物正处于I期临床试验阶段；对这些药物的临床前概况进行比较和对比，并讨论这种潜在的革命性癌症治疗方法面临的一些机遇和挑战。
对有关XL-844、AZD7762和PF-477736的出版物和报告进行综述。
结果/结论：Chk激酶是DNA损伤识别和反应途径的一部分，因此是有吸引力的靶点。靶向关卡激酶的药物在临床前已显示出令人印象深刻的证据，表明这种方法将提供肿瘤特异性增效剂，可能具有广泛的治疗用途。
