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Molecular Construction and Anti-Bladder Cancer Study of Novel TOP1/PARP1 Dual-Target Inhibitors
Wenchao Wang1, Dan Li2, Jin Liu2
1Urology & Nephrology Center, Department of Urology, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, Zhejiang310014, China.
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.
Insights
New dual-target inhibitors overcome chemotherapy resistance in bladder cancer. Compound D5 blocks DNA repair, converting single-strand breaks to lethal double-strand breaks, showing potent antitumor effects.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Bladder cancer presents high global incidence and mortality.
- Conventional DNA-damaging chemotherapies (e.g., cisplatin) face efficacy limitations due to acquired resistance.
- Upregulation of Poly (ADP-ribose) polymerase 1 (PARP1) is a key mechanism diminishing therapeutic effects by repairing DNA single-strand breaks (SSBs).
Purpose of the Study:
- To design and synthesize novel inhibitors targeting both Topoisomerase 1 (TOP1) and PARP1.
- To develop a therapeutic strategy that converts repairable SSBs into lethal double-strand breaks (DSBs) to overcome chemoresistance.
Main Methods:
- Synthesis of a series of united TOP1/PARP1 inhibitors.
- Evaluation of dual-target inhibitory activity of synthesized compounds.
- Assessment of compound efficacy in overcoming cisplatin resistance in vitro and in vivo.
Main Results:
- Compound D5 demonstrated excellent dual-target inhibitory activity against TOP1 and PARP1.
- D5 effectively overcame cisplatin resistance in preclinical models.
- Significant antitumor efficacy was observed in vitro and in vivo, with a Tumor Growth Inhibition (TGI) of 65.7%.
Conclusions:
- Compound D5, a novel TOP1/PARP1 inhibitor, effectively induces SSBs and inhibits their repair.
- D5 represents a promising therapeutic agent for overcoming resistance to conventional DNA-damaging chemotherapies in bladder cancer.
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