Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA; Department of Pharmaceutical Sciences and Experimental Therapeutics, Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242, USA.
Cell Chem Biol. 2017 Sep 21;24(9):1101-1119. doi: 10.1016/j.chembiol.2017.08.027.
To maintain stable genomes and to avoid cancer and aging, cells need to repair a multitude of deleterious DNA lesions, which arise constantly in every cell. Processes that support genome integrity in normal cells, however, allow cancer cells to develop resistance to radiation and DNA-damaging chemotherapeutics. Chemical inhibition of the key DNA repair proteins and pharmacologically induced synthetic lethality have become instrumental in both dissecting the complex DNA repair networks and as promising anticancer agents. The difficulty in capitalizing on synthetically lethal interactions in cancer cells is that many potential targets do not possess well-defined small-molecule binding determinates. In this review, we discuss several successful campaigns to identify and leverage small-molecule inhibitors of the DNA repair proteins, from PARP1, a paradigm case for clinically successful small-molecule inhibitors, to coveted new targets, such as RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.
为了维持稳定的基因组并避免癌症和衰老，细胞需要修复大量不断在每个细胞中产生的有害 DNA 损伤。然而，在正常细胞中支持基因组完整性的过程使癌细胞能够对辐射和 DNA 损伤的化疗药物产生耐药性。关键 DNA 修复蛋白的化学抑制和药理学诱导的合成致死性已成为解析复杂的 DNA 修复网络的有力工具，并具有广阔的抗癌应用前景。在癌细胞中利用合成致死相互作用的困难在于，许多潜在的靶标并不具有明确的小分子结合决定因素。在这篇综述中，我们讨论了几个成功的案例，以确定和利用 DNA 修复蛋白的小分子抑制剂，从 PARP1 这个在临床上成功的小分子抑制剂范例，到 RAD51 重组酶、RAD52 DNA 修复蛋白、MRE11 核酸酶和 WRN DNA 解旋酶等令人垂涎的新靶标。
