Design, synthesis, and biological evaluation of hydrophobic-tagged poly (ADP-ribose) polymerase 1 (PARP1) degraders.

Given its critical role in mediating the DNA damage response and repair, Poly (ADP-ribose) polymerase-1 (PARP1) has been established as a significant therapeutic target for cancer and a multitude of other human diseases. In this study, a novel series of hydrophobic tagging (HyT) derivatives were developed through design, synthesis, and evaluation to induce the degradation of PARP1. Leading compound 11e demonstrated significant efficacy in the triple-negative breast cancer cell line MDA-MB-231, potently degrading PARP1 in a concentration- and time-dependent manner, thereby effectively inhibiting cancer cell proliferation and migration. Moreover, a degradation of PARP1 was induced by 11e in various BRCA1/2-proficient carcinoma-derived lines, with potency observed at low compound levels. In conclusion, compound 11e, a novel and highly effective PARP1 degrading agent, displays superior degradation capability and holds considerable promise for future clinical applications.