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ID: ALA5241106
Journal: J Med Chem
Title: Discovery of a Dual Tubulin and Poly(ADP-Ribose) Polymerase-1 Inhibitor by Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, and Biological Evaluation.
Authors: Zheng L, Ren R, Sun X, Zou Y, Shi Y, Di B, Niu MM.
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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