Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1
Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1
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DOI：
10.1158/1535-7163.mct-07-2391
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发表时间：
2008-08-01
影响因子：
5.7
通讯作者：
Anderes, Kenna
中科院分区：
文献类型：
--
作者：
Blasina, Alessandra;Hallin, Jill;Anderes, Kenna
检查点存在于细胞周期的所有阶段，被认为是维持基因组完整性的守门人。许多用于治疗癌症的常规药剂对基因组造成损伤并激活细胞周期检查点。许多肿瘤在肿瘤抑制因子p53中有缺陷，因此缺乏功能性G1检查点。然而，在这些肿瘤中，S-G（2）检查点保持完整，并响应DNA损伤，阻止细胞周期进程，从而为DNA修复提供时间。检查点激酶1（Checkpoint kinase 1，Chk 1）是DNA损伤反应途径中的关键元件，在S-G（2）期检查点中起着至关重要的作用。抑制Chk 1代表了一种治疗策略，用于通过超越肿瘤细胞针对DNA导向化疗剂诱导的致死性损伤的最后检查点防御来产生“合成致死”应答。Chk 1抑制与旨在利用正常细胞和癌细胞之间的分子差异的新兴靶向治疗一致。将Chk 1抑制剂添加到DNA损伤细胞毒性疗法中选择性地靶向具有内在检查点缺陷的肿瘤，同时最大限度地减少检查点活性正常细胞的毒性。PF-00477736被鉴定为一种强效、选择性ATP竞争性小分子抑制剂，可抑制Chk 1，Ki为0.49 nM。PF-00477736消除了DNA损伤诱导的细胞周期阻滞，并增强了临床重要化疗药物（包括吉西他滨和卡铂）的细胞毒性。在异种移植物中，PF-00477736以剂量依赖性方式增强吉西他滨的抗肿瘤活性。PF-00477736联合给药耐受性良好，未加重通常与细胞毒性药物相关的副作用。
Checkpoints are present in all phases of the cell cycle and are regarded as the gatekeepers maintaining the integrity of the genome. Many conventional agents used to treat cancer impart damage to the genome and activate cell cycle checkpoints. Many tumors are defective in the tumor suppressor p53 and therefore lack a functional G, checkpoint. In these tumors, however, the S-G(2) checkpoints remain intact and, in response to DNA damage, arrest cell cycle progression allowing time for DNA repair. Checkpoint kinase 1 (Chk1) is a key element in the DNA damage response pathway and plays a crucial role in the S-G(2)-phase checkpoints. Inhibiting Chk1 represents a therapeutic strategy for creating a "synthetic lethal" response by overriding the last checkpoint defense of tumor cells against the lethal damage induced by DNA-directed chemotherapeutic agents. Chk1 inhibition is consistent with emerging targeted therapies aiming to exploit molecular differences between normal and cancer cells. Adding a Chk1 inhibitor to DNA-damaging cytotoxic therapy selectively targets tumors with intrinsic checkpoint defects while minimizing toxicity in checkpoint-competent normal cells. PF-00477736 was identified as a potent, selective ATP-competitive small-molecule inhibitor that inhibits Chk1 with a K-i of 0.49 nM. PF-00477736 abrogates cell cycle arrest induced by DNA damage and enhances cytotoxicity of clinically important chemotherapeutic agents, including gemcitabine and carboplatin. In xenografts, PF-00477736 enhanced the antitumor activity of gemcitabine in a dose-dependent manner. PF-00477736 combinations were well tolerated with no exacerbation of side effects commonly associated with cytotoxic agents.