Identification and Optimization of Novel Dual PARP/Tubulin Colchicine-Binding Site Inhibitors for Cancer Therapy
Zhouyan Liu, Tong Li, Yajing Chen, Dong Wei, Yueling Zhou, Cheng Chen, Yanyan Feng, Ziwei Tang, Zheying Zhu, Jinyi Xu, Jichao ChenAbstract
Dual targeting of poly(ADP-ribose) polymerase (PARP) and the colchicine-binding site (CBS) of tubulin represents a promising strategy to overcome tumor heterogeneity and acquired resistance. Herein, a series of benzofused heterocyclic carboxamide derivatives were designed and synthesized as novel dual PARP/CBS inhibitors. Structure−activity relationship studies identified D13 as the most potent lead, demonstrating low-nanomolar antiproliferative activities (IC50 = 2−15 nM) across multiple cancer cell lines with high selectivity over normal cells. D13 inhibited PARP1/2 enzymatic activity and suppressed tubulin polymerization via CBS binding. D13 also induced G2/M arrest, DNA damage, and apoptosis, while blocking cell migration and tube formation. In an MDA-MB-231 xenograft model, D13 at 20 mg/kg achieved 72.3% tumor growth inhibition with dose-dependent efficacy and good tolerability, outperforming veliparib, phenstatin, and their combination. These findings validate dual PARP/CBS inhibition as a viable therapeutic strategy and support further development of D13 as an anticancer lead.