Liu Juanjuan, Geng Yifei, Jiang Su, Guan Lixia, Gao Junyi, Niu Miao-Miao, Li Jindong
Department of Pharmacy, Taizhou School of Clinical Medicine, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2024 Nov 29;15:1454957. doi: 10.3389/fphar.2024.1454957. eCollection 2024.
Given that overexpression of Poly (ADP-ribose) polymerase-1 (PARP1) and Neuropilin-1 (NRP1) is implicated in the pathogenesis of human breast cancer, the design of dual PARP1/NRP1 inhibitors has wide therapeutic prospect. However, there have been no reports of such inhibitors so far. Herein, we discovered novel small molecule inhibitors that simultaneously target PARP1 and NRP1 using structure-based virtual screening for the treatment of breast cancer. Notably, PPNR-4 was the most potent inhibitor targeting PARP1 (IC = 7.71 ± 0.39 nM) and NRP1 (IC = 24.48 ± 2.16 nM). PPNR-4 showed high affinity and binding stability to PARP1 and NRP1. The cytotoxicity assays showed that PPNR-4 demonstrated significant antiproliferative activity on MDA-MB-231 cells (IC = 0.21 μM) without effect on normal human cells. experiments exhibited that PPNR-4 showed more effective than the positive controls in inhibiting the growth of tumors. Overall, these data suggest that PPNR-4 is an effective antitumor candidate and deserves further research.
鉴于聚（ADP - 核糖）聚合酶 -1（PARP1）和神经纤毛蛋白 -1（NRP1）的过表达与人类乳腺癌的发病机制有关，双PARP1/NRP1抑制剂的设计具有广阔的治疗前景。然而，迄今为止尚无此类抑制剂的报道。在此，我们利用基于结构的虚拟筛选发现了同时靶向PARP1和NRP1的新型小分子抑制剂，用于治疗乳腺癌。值得注意的是，PPNR - 4是靶向PARP1（IC = 7.71 ± 0.39 nM）和NRP1（IC = 24.48 ± 2.16 nM）的最有效抑制剂。PPNR - 4对PARP1和NRP1表现出高亲和力和结合稳定性。细胞毒性试验表明，PPNR - 4对MDA - MB - 231细胞具有显著的抗增殖活性（IC = 0.21 μM），而对正常人细胞无影响。实验表明，PPNR - 4在抑制肿瘤生长方面比阳性对照更有效。总体而言，这些数据表明PPNR - 4是一种有效的抗肿瘤候选物，值得进一步研究。
