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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1454957

Discovery of novel PARP1/NRP1 dual-targeting inhibitors with strong antitumor potency

Provisionally accepted
Juanjuan Liu Juanjuan Liu 1,2Yifei Geng Yifei Geng 3Su Jiang Su Jiang 2Lixia Guan Lixia Guan 3Junyi Gao Junyi Gao 2Miao-Miao Niu Miao-Miao Niu 3Jindong Li Jindong Li 2*
  • 1 The Affiliated Taizhou People's Hospital, Nanjing Medical University, Taizhou, China
  • 2 The Affliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China
  • 3 China Pharmaceutical University, Nanjing, Jiangsu Province, China

The final, formatted version of the article will be published soon.

    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 (IC50 = 7.71 ± 0.39 nM) and NRP1 (IC50 = 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 (IC50 = 0.21 μM) without effect on normal human cells. In vivo 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.

    Keywords: Poly (ADP-ribose) polymerase-1 (PARP1), Neuropilin-1 (NRP1), breast cancer, dual-targeting inhibitors, Structure-based virtual screening

    Received: 26 Jun 2024; Accepted: 15 Nov 2024.

    Copyright: © 2024 Liu, Geng, Jiang, Guan, Gao, Niu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jindong Li, The Affliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, China

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