Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, PR China.
Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, 410011, PR China.
Eur J Med Chem. 2020 Oct 1;203:112570. doi: 10.1016/j.ejmech.2020.112570. Epub 2020 Jul 15.
Poly(ADP-ribose) Polymerase 1 (PARP1), one of the most investigated 18 membered PARP family enzymes, is involved in a variety of cellular functions including DNA damage repair, gene transcription and cell apoptosis. PARP1 can form a PARP1(ADP-ribose) polymers, then bind to the DNA damage gap to recruit DNA repair proteins, and repair the break to maintain genomic stability. PARP1 is highly expressed in tumor cells, so the inhibition of PARP1 can block DNA repair, promote tumor cell apoptosis, and exert antitumor activity. To date, four PARP1 inhibitors namely olaparib, rucaparib, niraparib and talazoparib, have been approved by Food and Drug Administration (FDA) for treating ovarian cancer and breast cancer with BRCA1/2 mutation. These drugs have showed super advantages over conventional chemotherapeutic drugs with low hematological toxicity and slowly developed drug resistance. In this article, we summarize and analyze the structure features of PARP1, the biological functions and antitumor mechanisms of PARP1 inhibitors. Importantly, we suggest that establishing a new structure-activity relationship of developed PARP1 inhibitors via substructural searching and the matched molecular pair analysis would accelerate the process in finding more potent and safer PARP1 inhibitors.
聚（ADP-核糖）聚合酶 1（PARP1）是研究最为广泛的 18 个聚 PARP 家族酶之一，参与多种细胞功能，包括 DNA 损伤修复、基因转录和细胞凋亡。PARP1 可以形成 PARP1（ADP-核糖）聚合物，然后结合到 DNA 损伤缺口，招募 DNA 修复蛋白，修复断裂以维持基因组稳定性。PARP1 在肿瘤细胞中高度表达，因此抑制 PARP1 可以阻断 DNA 修复，促进肿瘤细胞凋亡，发挥抗肿瘤活性。迄今为止，四种 PARP1 抑制剂，即奥拉帕利、鲁卡帕利、尼拉帕利和他拉唑帕利，已被美国食品和药物管理局（FDA）批准用于治疗携带 BRCA1/2 突变的卵巢癌和乳腺癌。这些药物与传统化疗药物相比具有更低的血液学毒性和较慢的耐药性，具有明显优势。本文总结和分析了 PARP1 的结构特征、PARP1 抑制剂的生物学功能和抗肿瘤机制。重要的是，我们建议通过亚结构搜索和匹配分子对分析建立新的 PARP1 抑制剂结构活性关系，将加速发现更有效和更安全的 PARP1 抑制剂的进程。
