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Review Article

通过丝氨酸/苏氨酸激酶抑制剂打破DNA损伤反应，改善癌症治疗

卷 26, 期 8, 2019

页: [1425 - 1445] 页: 21

弟呕挨: 10.2174/0929867325666180117102233

价格: $65

摘要

内源性和外源性多种来源可能诱导DNA损伤和DNA复制应激。细胞已经形成DNA损伤应答（DDR）信号通路，以维持基因组稳定性并有效地检测和修复DNA损伤。丝氨酸/苏氨酸激酶如共济失调 - 毛细血管扩张症（ATM）和共济失调 - 毛细血管扩张症和Rad3相关（ATR）是DDR的主要调节因子，因为感知停滞的DNA复制叉后，DNA双链或单链断裂，可能直接磷酸化并激活其下游靶标，其在DNA修复，细胞周期停滞和凋亡细胞死亡中起关键作用。有趣的是，DDR信号网络的关键组成部分可能通过两种截然不同的潜在方法构成抗癌治疗的有吸引力的目标：作为化学和放射增敏剂，以提高目前使用的基因毒性治疗的有效性，或作为单一药物通过合成利用癌症细胞中的DDR缺陷致命的方法。此外，最新数据报道，丝氨酸/苏氨酸蛋白激酶R（PKR）样内质网激酶（PERK）也与癌症的发展和进展密切相关。因此，利用小分子丝氨酸/苏氨酸激酶抑制剂可提供新颖的，开创性的抗癌治疗策略。目前，已发现一系列针对ATM，ATR和PERK抑制剂的强效，高选择性，但在上述研究之后，其未来的临床应用需要进一步的研究。

关键词: 癌症，DNA损伤反应，ATM，ATR，PERK，激酶抑制剂，癌症治疗。

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