Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair.
Recent Advances in the Development of Non-PIKKs Targeting Small Molecule Inhibitors of DNA Double-Strand Break Repair.
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DOI：
10.3389/fonc.2022.850883
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发表时间：
2022
影响因子：
4.7
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中科院分区：
文献类型：
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绝大多数癌症患者在治疗过程中接受DNA损伤药物或电离辐射（IR），但这些疗法的疗效受到DNA修复和DNA损伤反应（DDR）途径的影响。在许多癌症亚型中观察到DNA修复和DDR的畸变，并且可以促进从头致癌、基因组不稳定性和随后对当前癌症治疗的抗性。此外，停滞或塌陷的DNA复制叉对双链DNA断裂（DSB）修复系统提出了独特的挑战。在各种可诱导的DNA损伤中，DSB是最致命的，因此在癌症治疗中是理想的。在哺乳动物细胞中，DSB通常通过易错非同源末端连接途径（NHEJ）或高保真同源定向修复（HDR）途径修复。使用小分子抑制剂靶向DSB修复途径提供了一种有前途的机制，以协同DNA损伤药物和IR，而选择性抑制NHEJ途径可以诱导HDR缺陷癌症亚型的合成致死性。NHEJ途径和替代DSB修复途径的选择性抑制剂也可能在未来用于精确基因组编辑，以直接修复HDR途径产生的DSB。在这篇综述中，我们重点介绍了NHEJ，HDR和次要备用SSA和alt-NHEJ DSB修复途径的非磷脂酰肌醇3-激酶相关激酶（非PIKKs）成员抑制剂的最新进展。本综述中描述的抑制剂靶向DSB修复的非PIKK介导剂，包括Ku 70/80、Artemis、DNA连接酶IV、XRCC 4、MRN复合物、RPA、RAD 51、RAD 52、ERCC 1-XPF、解旋酶和DNA聚合酶θ。虽然DDR PIKK仍然被强烈追求为治疗靶标，但非PIKK的小分子抑制代表了药物发现中的新兴机会，其提供了影响癌症治疗的相当大的潜力。
The vast majority of cancer patients receive DNA-damaging drugs or ionizing radiation (IR) during their course of treatment, yet the efficacy of these therapies is tempered by DNA repair and DNA damage response (DDR) pathways. Aberrations in DNA repair and the DDR are observed in many cancer subtypes and can promote de novo carcinogenesis, genomic instability, and ensuing resistance to current cancer therapy. Additionally, stalled or collapsed DNA replication forks present a unique challenge to the double-strand DNA break (DSB) repair system. Of the various inducible DNA lesions, DSBs are the most lethal and thus desirable in the setting of cancer treatment. In mammalian cells, DSBs are typically repaired by the error prone non-homologous end joining pathway (NHEJ) or the high-fidelity homology directed repair (HDR) pathway. Targeting DSB repair pathways using small molecular inhibitors offers a promising mechanism to synergize DNA-damaging drugs and IR while selective inhibition of the NHEJ pathway can induce synthetic lethality in HDR-deficient cancer subtypes. Selective inhibitors of the NHEJ pathway and alternative DSB-repair pathways may also see future use in precision genome editing to direct repair of resulting DSBs created by the HDR pathway. In this review, we highlight the recent advances in the development of inhibitors of the non-phosphatidylinositol 3-kinase-related kinases (non-PIKKs) members of the NHEJ, HDR and minor backup SSA and alt-NHEJ DSB-repair pathways. The inhibitors described within this review target the non-PIKKs mediators of DSB repair including Ku70/80, Artemis, DNA Ligase IV, XRCC4, MRN complex, RPA, RAD51, RAD52, ERCC1-XPF, helicases, and DNA polymerase θ. While the DDR PIKKs remain intensely pursued as therapeutic targets, small molecule inhibition of non-PIKKs represents an emerging opportunity in drug discovery that offers considerable potential to impact cancer treatment.
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影响因子：
4.7
作者：
Baptisteila, Antuani Rafael;Landemberger, Michele Christine;Martins, Ilma Regina
通讯作者：
Martins, Ilma Regina
影响因子：
16.8
作者：
Bhat KP;Cortez D
通讯作者：
Cortez D
影响因子：
4.8
作者：
Asan, Alparslan;Skoko, John J.;Neumann, Carola A.
通讯作者：
Neumann, Carola A.
影响因子：
7.3
作者：
Budke, Brian;Kalin, Jay H.;Pawlowski, Michal;Zelivianskaia, Anna S.;Wu, Megan;Kozikowski, Alan P.;Connell, Philip P.
通讯作者：
Connell, Philip P.
影响因子：
8.8
作者：
通讯作者：
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