Molecular Construction and Anti-Bladder Cancer Study of Novel TOP1/PARP1 Dual-Target Inhibitors.

Authors

Wenchao Wang, Dan Li, Jin Liu, Lei Li, Qi Zhang, Facai Zhang, Yang Liu, Yifan Zhang, Shuai Meng, Xuyang Shi, Hong Wang, Qingyong Li, Dahong Zhang, Zujie Mao

Published in

Journal of medicinal chemistry. Jul 27, 2026. Epub Jul 27, 2026.

Abstract

Bladder cancer is a malignant tumor with a high incidence and mortality worldwide. Clinically, DNA-damaging agents such as cisplatin, irinotecan, and gemcitabine are commonly used, but their efficacy is often limited by acquired resistance. A key resistance mechanism involves the upregulation of PARP1 in response to drug-induced DNA single-strand breaks (SSBs), which diminishes the therapeutic effect. To overcome this obstacle, we designed and synthesized a series of united TOP1/PARP1 inhibitors that simultaneously induce SSBs via TOP1 inhibition and block their repair via PARP1 inhibition, converting repairable SSBs to lethal double-strand breaks (DSBs). Among these, compound D5 exhibited excellent dual-target inhibitory activity and effectively overcame cisplatin resistance, demonstrating potent antitumor efficacy in vitro and in vivo (TGI = 65.7%). Collectively, D5 represents a promising TOP1/PARP1 inhibitor for overcoming resistance to conventional DNA-damaging chemotherapies.

PMID:
42504569
Bibliographic data and abstract were imported from PubMed on 27 Jul 2026.

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