Discovery of a Dual Tubulin and Poly(ADP-Ribose) Polymerase-1 Inhibitor by Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, and Biological Evaluation

  • J Med Chem. 2021 Nov 11;64(21):15702-15715. doi: 10.1021/acs.jmedchem.1c00932.
Lufeng Zheng  1 ,  Ren Ren  2 ,  Xiaolian Sun  3 ,  Yunting Zou  2 ,  Yiru Shi  2 ,  Bin Di  2 ,  Miao-Miao Niu  2
Affiliations
  • 1. School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing 210009, China.
  • 2. Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, Nanjing 210009, China.
  • 3. State Key Laboratory of Natural Medicines, Key Laboratory of Drug Quality Control and Pharmacovigilance, Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009, China.
PMID: 34670362 DOI: 10.1021/acs.jmedchem.1c00932
Abstract

Dual inhibition of tubulin and poly(ADP-ribose) polymerase-1 (PARP-1) may become an attractive approach for Cancer therapy. Here, we discover a dual tubulin/PARP-1 inhibitor (termed as TP-3) using structure-based virtual screening. TP-3 shows strong dual inhibitory effects on both tubulin and PARP-1. Cellular assays reveal that TP-3 shows superior antiproliferative activities against human Cancer cells, including breast, liver, ovarian, and cervical cancers. Further studies indicate that TP-3 plays an antitumor role through multiple mechanisms, including the disturbance of the microtubule network and the PARP-1 DNA repairing function, accumulation of DNA double-strand breaks, inhibition of the tube formation, and induction of G2/M cell cycle arrest and Apoptosis. In vivo assessment indicates that TP-3 inhibits the growth of MDA-MB-231 xenograft tumors in nude mouse with no notable side effects. These data demonstrate that TP-3 is a dual-targeting, high-efficacy, and low-toxic antitumor agent.

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