Coixol derivatives induce DNA damage by targeting PARP1

Area of Science:

• Medicinal Chemistry
• Cancer Biology
• Pharmacology

Background:

• Poly (ADP-ribose) polymerase 1 (PARP1) is a key enzyme in DNA repair, making it a significant target for cancer therapy.
• Identifying novel inhibitors with improved efficacy and reduced side effects is crucial for advancing cancer treatment.

Purpose of the Study:

• To identify and design novel PARP1 inhibitors using computational methods and chemical synthesis.
• To evaluate the anti-cancer potential of synthesized compounds, particularly compound 9a, in preclinical models.

Main Methods:

• Virtual screening and computer-aided drug design (CADD) were employed to identify potential PARP1 inhibitors.
• A series of coixol derivatives were synthesized and their PARP1 inhibitory activity was assessed.
• Structure-activity relationship (SAR) analysis was performed to optimize inhibitor efficacy.
• In vitro assays using breast cancer MDA-MB-231 and ovarian cancer A2780 cells were conducted.
• In vivo studies and mechanistic investigations (apoptosis, cell cycle, ROS, migration) were performed.

Main Results:

• Coixol was identified as a natural product targeting PARP1.
• Compound 9a demonstrated significant PARP1 inhibitory activity and potent anti-proliferative effects.
• Compound 9a exhibited superior efficacy compared to positive control drugs in both in vitro and in vivo experiments.
• Mechanistic studies revealed that 9a induces apoptosis, DNA damage, S-phase arrest, increases ROS, and inhibits cell migration and proliferation.

Conclusions:

• Compound 9a represents a novel structural framework for developing effective PARP1 inhibitors.
• KWZY-9a (compound 9a) holds significant potential for future cancer therapeutic applications.
• The findings support the advancement of 9a as a promising candidate for cancer treatment development.