Coixol derivatives induce DNA damage by targeting PARP1.

Through virtual screening, coixol, a natural product targeted PARP1, was identified, and a series of derivatives with PARP1 inhibitory activity were designed based on CADD and successfully synthesized. SAR analysis revealed that compound 9a exhibited promising PARP1 inhibitory activity and demonstrated significant anti-proliferative effects in both breast cancer MDA-MB-231 and ovarian cancer A2780 cells. Notably, 9a outperformed the positive control drugs in both in vitro and in vivo experiments. Biological mechanistic studies further elucidated that 9a could induce apoptosis and DNA damage, arrest the cell cycle at the S phase, increase intracellular ROS levels, and inhibit cell migration and proliferation. In summary, 9a, encoded with KWZY-9a, offers a novel structural framework for the development of PARP1 inhibitors, holding great potential for future cancer therapies.