Targeting protein-protein interactions in the DNA damage response pathways for cancer chemotherapy.
Targeting protein-protein interactions in the DNA damage response pathways for cancer chemotherapy.
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DOI：
10.1039/d1cb00101a
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发表时间：
2021-08-05
影响因子：
4.1
通讯作者：
Korzhnev DM
中科院分区：
文献类型：
--
作者：
McPherson KS;Korzhnev DM
细胞DNA损伤反应（DDR）是一个广泛的信号网络，协调DNA损伤识别、修复和避免、细胞周期进展和细胞死亡。DDR改变是癌症的一个标志，其中一种DDR能力的缺失通常通过对其他途径的依赖来弥补，从而赋予癌细胞生存和生长优势。靶向这些DDR通路为癌症治疗的发展提供了多种机会。传统的药物发现主要集中在阻断酶活性位点的催化抑制剂上，这限制了DDR途径中潜在药物靶点的数量。这篇综述文章描述了针对DDR网络中必需蛋白-蛋白相互作用（PPIs）的癌症治疗的新方法。本文讨论了基于结构的小分子PPI抑制剂设计的总体策略，随后概述了主要的DNA损伤传感、DNA修复和DNA损伤耐受途径，并特别关注了抗癌药物设计的PPI靶点。总结了现有的DDR PPIs小分子抑制剂选择性杀死癌细胞和/或使癌症对一线基因毒性治疗敏感，并提出了一系列新的PPI靶点，可能导致新型化疗药物的发展。本文综述了利用小分子抑制剂靶向DNA损伤反应（DDR）通路中的蛋白-蛋白相互作用作为设计新型癌症化疗药物的策略。
Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alteration is a hallmark of cancer, with the deficiency in one DDR capability often compensated by a dependency on alternative pathways endowing cancer cells with survival and growth advantage. Targeting these DDR pathways has provided multiple opportunities for the development of cancer therapies. Traditional drug discovery has mainly focused on catalytic inhibitors that block enzyme active sites, which limits the number of potential drug targets within the DDR pathways. This review article describes the emerging approach to the development of cancer therapeutics targeting essential protein–protein interactions (PPIs) in the DDR network. The overall strategy for the structure-based design of small molecule PPI inhibitors is discussed, followed by an overview of the major DNA damage sensing, DNA repair, and DNA damage tolerance pathways with a specific focus on PPI targets for anti-cancer drug design. The existing small molecule inhibitors of DDR PPIs are summarized that selectively kill cancer cells and/or sensitize cancers to front-line genotoxic therapies, and a range of new PPI targets are proposed that may lead to the development of novel chemotherapeutics. Targeting protein–protein interactions within the DNA damage response (DDR) pathways with small molecule inhibitors is reviewed here as a strategy to design novel cancer chemotherapeutics.
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影响因子：
3.5
作者：
Actis ML;Ambaye ND;Evison BJ;Shao Y;Vanarotti M;Inoue A;McDonald ET;Kikuchi S;Heath R;Hara K;Hashimoto H;Fujii N
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Fujii N
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作者：
Arkin MR;Tang Y;Wells JA
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Aguilar A;Lu J;Liu L;Du D;Bernard D;McEachern D;Przybranowski S;Li X;Luo R;Wen B;Sun D;Wang H;Wen J;Wang G;Zhai Y;Guo M;Yang D;Wang S
通讯作者：
Wang S
影响因子：
7.3
作者：
Bagnolini G;Milano D;Manerba M;Schipani F;Ortega JA;Gioia D;Falchi F;Balboni A;Farabegoli F;De Franco F;Robertson J;Pellicciari R;Pallavicini I;Peri S;Minucci S;Girotto S;Di Stefano G;Roberti M;Cavalli A
通讯作者：
Cavalli A