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

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.