Discovery of a Dual Tubulin and Neuropilin-1 (NRP1) Inhibitor with Potent In Vivo Anti-Tumor Activity via Pharmacophore-based Docking Screening, Structure Optimization, and Biological Evaluation

  • J Med Chem. 2023 Dec 14;66(23):16187-16200. doi: 10.1021/acs.jmedchem.3c01572.
Lufeng Zheng  1 ,  Yunting Zou  2 ,  Tianyuan Xie  1 ,  Xiuyuan Wu  3 ,  Yuchen Tan  3 ,  Shuang Mei  2 ,  Yifei Geng  2 ,  Shutong Chen  2 ,  Shengtao Xu  3 ,  Miao-Miao Niu  2
Affiliations
  • 1. School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 211198, China.
  • 2. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing 211198, China.
  • 3. Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
PMID: 38093696 DOI: 10.1021/acs.jmedchem.3c01572
Abstract

Dual inhibition of tubulin and neuropilin-1 (NRP1) may become an effective method for Cancer treatment by simultaneously killing tumor cells and inhibiting tumor angiogenesis. Herein, we identified dual tubulin/NRP1-targeting inhibitor TN-2, which exhibited good inhibitory activity against both tubulin polymerization (IC50 = 0.71 ± 0.03 μM) and NRP1 (IC50 = 0.85 ± 0.04 μM). Importantly, it significantly inhibited the viability of several human prostate tumor cell lines. Further mechanism studies indicated that TN-2 could inhibit tubulin polymerization and cause G2/M arrest, thereby inducing cell Apoptosis. It could also suppress cell tube formation, migration, and invasion. Moreover, TN-2 showed obvious antitumor effects on the PC-3 cell-derived xenograft model with negligible side effects and good pharmacokinetic profiles. These data demonstrate that TN-2 could be a promising dual-target chemotherapeutic agent for the treatment of prostate Cancer.

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