Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy.
Development and Evolution of DNA-Dependent Protein Kinase Inhibitors toward Cancer Therapy.
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DOI：
10.3390/ijms23084264
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发表时间：
2022-04-12
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
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作者：
DNA双链断裂（DSB）被认为是最有害的DNA损伤类型，其由电离辐射（IR）和抗癌药物的子集产生。DNA依赖性蛋白激酶（DNA-PK）由DNA-PK催化亚基（DNA-PKcs）和Ku 80-Ku 70异源二聚体组成，是DSB的分子传感器，通过非同源末端连接（NHEJ）在DSB的修复中发挥关键作用。缺乏DNA-PKcs的细胞对IR和几种DNA损伤剂表现出超敏反应。细胞对IR和DNA损伤剂的敏感性可以通过抑制DNA-PK来增强。已经开发了许多抑制DNA-PK的小分子。本文就靶向DNA-PK的抑制剂在肿瘤治疗中的应用进展作一综述。基于DNA-PK与磷脂酰肌醇3-激酶（PI 3 Ks）和PI 3 K相关激酶（PIKKs）（包括共济失调-毛细血管扩张突变型（ATM））的结构相似性，开发了大部分抑制剂。一些DNA-PK抑制剂，例如，NU 7026和NU 7441已广泛用于DNA-PK的细胞功能研究。最近开发的抑制剂，例如，M3814和AZD 7648正在进行临床试验，并即将与放疗和化疗联合用于癌症治疗。
DNA double-strand break (DSB) is considered the most deleterious type of DNA damage, which is generated by ionizing radiation (IR) and a subset of anticancer drugs. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a pivotal role in DSB repair through non-homologous end joining (NHEJ). Cells deficient for DNA-PKcs show hypersensitivity to IR and several DNA-damaging agents. Cellular sensitivity to IR and DNA-damaging agents can be augmented by the inhibition of DNA-PK. A number of small molecules that inhibit DNA-PK have been developed. Here, the development and evolution of inhibitors targeting DNA-PK for cancer therapy is reviewed. Significant parts of the inhibitors were developed based on the structural similarity of DNA-PK to phosphatidylinositol 3-kinases (PI3Ks) and PI3K-related kinases (PIKKs), including Ataxia-telangiectasia mutated (ATM). Some of DNA-PK inhibitors, e.g., NU7026 and NU7441, have been used extensively in the studies for cellular function of DNA-PK. Recently developed inhibitors, e.g., M3814 and AZD7648, are in clinical trials and on the way to be utilized in cancer therapy in combination with radiotherapy and chemotherapy.
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KU-0060648 通过 DNA-PKcs 依赖性和 DNA-PKcs 独立机制抑制肝细胞癌细胞。
影响因子：
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作者：
Chen MB;Zhou ZT;Yang L;Wei MX;Tang M;Ruan TY;Xu JY;Zhou XZ;Chen G;Lu PH
通讯作者：
Lu PH
影响因子：
5.6
作者：
Bürkel F;Jost T;Hecht M;Heinzerling L;Fietkau R;Distel L
通讯作者：
Distel L
影响因子：
5.7
作者：
Anastasia, Alessia;Dellavedova, Giulia;Bani, Maria Rosa
通讯作者：
Bani, Maria Rosa
DOI：
10.1158/1078-0432.ccr-13-1607
发表时间：
2014-03-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gil del Alcazar CR;Hardebeck MC;Mukherjee B;Tomimatsu N;Gao X;Yan J;Xie XJ;Bachoo R;Li L;Habib AA;Burma S
通讯作者：
Burma S
影响因子：
2.8
作者：
Chao, Olivia S.;Goodman, Oscar B., Jr.
通讯作者：
Goodman, Oscar B., Jr.