AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies
AZD7762, a novel checkpoint kinase inhibitor, drives checkpoint abrogation and potentiates DNA-targeted therapies
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DOI：
10.1158/1535-7163.mct-08-0492
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发表时间：
2008-09-01
影响因子：
5.7
通讯作者：
White, Anne M.
中科院分区：
文献类型：
--
作者：
Zabludoff, Sonya D.;Deng, Chun;White, Anne M.
来自细胞周期研究的见解导致了一种假设，即肿瘤可能对DNA损伤剂选择性敏感，从而提高抗肿瘤活性和更广泛的治疗范围。该理论依赖于观察到大多数肿瘤在G(1)-DNA损伤检查点途径上存在缺陷，导致依赖S和G(2)检查点进行DNA修复和细胞存活。S和G2检查点受检查点激酶1的调节，这是一种丝氨酸/苏氨酸激酶，在DNA损伤时被激活；因此，抑制检查点激酶1信号会损害DNA修复并增加肿瘤细胞的死亡。然而，正常组织有一个功能正常的G(1)检查点信号通路，允许DNA修复和细胞存活。在这里，我们描述了AZD7762的临床前概况，AZD7762是一种有效的ATP竞争性检查点激酶抑制剂，正在进行临床试验。AZD7762在体外和体内与DNA损伤剂结合使用已被广泛分析，并已被证明在几种不同的环境中增强反应，在这些环境中，抑制检查点激酶导致取消DNA损伤诱导的细胞周期停滞。在含有几种DNA损伤剂的多个异种移植模型中，已经观察到当AZD7762与DNA损伤剂联合使用时，抗肿瘤活性的剂量依赖性增强，进一步支持了检查点激酶抑制剂在各种情况下增强传统化疗和放射治疗的疗效和提高患者缓解率的潜力。
Insights from cell cycle research have led to the hypothesis that tumors may be selectively sensitized to DNA-damaging agents resulting in improved antitumor activity and a wider therapeutic margin. The theory relies on the observation that the majority of tumors are deficient in the G(1)-DNA damage checkpoint pathway resulting in reliance on S and G(2) checkpoints for DNA repair and cell survival. The S and G2 checkpoints are regulated by checkpoint kinase 1, a serine/threonine kinase that is activated in response to DNA damage; thus, inhibition of checkpoint kinase 1 signaling impairs DNA repair and increases tumor cell death. Normal tissues, however, have a functioning G(1) checkpoint signaling pathway allowing for DNA repair and cell survival. Here, we describe the preclinical profile of AZD7762, a potent ATP-competitive checkpoint kinase inhibitor in clinical trials. AZD7762 has been profiled extensively in vitro and in vivo in combination with DNA-damaging agents and has been shown to potentiate response in several different settings where inhibition of checkpoint kinase results in the abrogation of DNA damage-induced cell cycle arrest. Dose-dependent potentiation of antitumor activity, when AZD7762 is administered in combination with DNA-damaging agents, has been observed in multiple xenograft models with several DNA-damaging agents, further supporting the potential of checkpoint kinase inhibitors to enhance the efficacy of both conventional chemotherapy and radiotherapy and increase patient response rates in a variety of settings.