Targeting DNA-Dependent Protein Kinase for Cancer Therapy
Targeting DNA-Dependent Protein Kinase for Cancer Therapy
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DOI：
10.1002/cmdc.201700143
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发表时间：
2017-06-21
期刊：
影响因子：
3.4
通讯作者：
Cano, Celine
中科院分区：
文献类型：
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作者：
Harnor, Suzannah J.;Brennan, Alfie;Cano, Celine
DNA依赖性蛋白激酶（DNA-PK）的催化活性对于其修复致死性DNA双链断裂（DSB）的能力至关重要。这包括修复由氧化应激、癌基因诱导的转录或癌细胞治疗性治疗引起的DSB病变。有了这些知识，已经进行了许多尝试，以确定DNA-PK活性的小分子抑制剂作为诱导肿瘤化学和放射增敏的方法。本文综述了已知的可逆和不可逆抑制剂的结构，包括那些基于色烯-4-酮，芳基吗啉，苯甲醛支架。DNA-PK催化抑制剂，如VX-984（8-[（1 S）-2-[[6-（2-甲氧基苯基）-2-氧代-3-甲基-2-氧代-3-氧代-3-氧代-4-氧代-3-氧代-3-氧代-4-氧代-3-氧代-3-氧代-4-氧代-3-氧代-3-氧代-4-氧代-3-氧代-3-氧代-4-氧代-3-氧代-4-氧代-3-氧代-3（4，6-二氘代-2-甲基嘧啶-5-基）嘧啶-4-基]氨基]-1-甲基乙基]喹啉-4-甲酰胺）和M3814（（S）-[2-氯-4-氟-5-甲基嘧啶-4-基]氨基]喹啉-4-甲酰胺）。（7-吗啉代喹唑啉-4-基）苯基]-（6-甲氧基哒嗪-3-基）甲醇）的研究已经进入临床开发阶段，这将有助于进一步推进我们对这种方法是否是治疗癌症的有希望的治疗策略的理解。
The catalytic activity of DNA-dependent protein kinase (DNA-PK) is critical to its ability to repair lethal DNA double-strand breaks (DSBs). This includes repair of DSB lesions resulting from oxidative stress, oncogene-induced transcription, or following therapeutic treatment of cancer cells. Armed with this knowledge, many attempts have been made to identify small-molecule inhibitors of DNA-PK activity as an approach to induce tumour chemo-and radiosensitisation. This review examines the structures of known reversible and irreversible inhibitors, including those based on chromen-4-one, arylmor-pholine, and benzaldehyde scaffolds. DNA-PK catalytic inhibitors, such as VX-984 (8-[(1S)-2-[[6-(4,6-dideuterio-2-methylpyrimidin-5-yl)pyrimidin-4-yl]amino]-1-methylethyl] quinoline-4carboxamide) and M3814 ((S)-[2-chloro-4-fluoro-5-(7-morpholinoquinazolin-4-yl)phenyl]-(6-methoxypyridazin-3-yl) methanol), have now progressed into clinical development which should help to further advance our understanding of whether this approach is a promising therapeutic strategy for the treatment of cancer.