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

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Bladder cancer presents a significant global health challenge with high mortality rates.
• Conventional DNA-damaging chemotherapies like cisplatin are often hindered by acquired resistance.
• Upregulation of Poly (ADP-ribose) polymerase 1 (PARP1) is a key mechanism diminishing therapeutic effectiveness 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 drug resistance.
• To evaluate the efficacy of these dual-target inhibitors against cisplatin-resistant bladder cancer.

Main Methods:

• Synthesis of a series of united TOP1/PARP1 inhibitors.
• In vitro and in vivo evaluation of compound D5's antitumor activity.
• Assessment of D5's ability to induce SSBs via TOP1 inhibition and block repair via PARP1 inhibition.

Main Results:

• Compound D5 demonstrated potent dual-target inhibitory activity against TOP1 and PARP1.
• D5 effectively overcame cisplatin resistance in bladder cancer models.
• Significant antitumor efficacy was observed in vitro and in vivo, with a tumor growth inhibition (TGI) of 65.7%.

Conclusions:

• Compound D5 acts as a promising bifunctional inhibitor of TOP1 and PARP1.
• This novel therapeutic approach effectively overcomes resistance to conventional DNA-damaging chemotherapies.
• D5 holds potential for treating advanced or resistant bladder cancer.