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

• Published in: Journal of medicinal chemistry Vol. 64; no. 21; pp. 15702 - 15715
• Main Authors: Zheng, Lufeng, Ren, Ren, Sun, Xiaolian, Zou, Yunting, Shi, Yiru, Di, Bin, Niu, Miao-Miao
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11.11.2021
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; DNA Breaks, Double-Stranded; Drug Discovery; Drug Screening Assays, Antitumor; G2 Phase Cell Cycle Checkpoints - drug effects; Humans; Mice; Mice, Nude; Models, Molecular; Molecular Docking Simulation; Poly(ADP-ribose) Polymerase Inhibitors - chemistry; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Tubulin Modulators - chemistry; Tubulin Modulators - pharmacology; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00932

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.