Rational design, synthesis, and biological evaluation of novel PARP1 degraders for colon cancer therapy

Poly (ADP-ribose) polymerase 1 (PARP1) is a validated therapeutic target for cancer treatment; however, conventional PARP inhibitors are limited by their occupancy-driven mechanism and acquired resistance. To explore an alternative strategy, a series of hydrophobic tagging-based PARP1 degraders were designed and synthesized by conjugating hydrophobic moieties to olaparib through linkers of varying lengths. Structure-activity relationship studies identified compound 7i as the most promising degrader, exhibiting potent antiproliferative activity against SW620 cells (IC₅₀ = 5.62 ± 0.41 μM) and efficient PARP1 degradation with a DC₅₀ value of 4.31 ± 0.67 μM. Compound 7i induced rapid, concentration- and time-dependent degradation of PARP1. Mechanistic studies suggested that 7i-mediated degradation was dependent on the ubiquitin-proteasome system. In addition, pharmacological inhibition of HSP70 and HSP90 partially restored PARP1 protein levels, suggesting that chaperone-associated protein quality control pathways may contribute to the degradation process. Compound 7i effectively reduced PARP1 expression in multiple colorectal cancer cell lines and induced apoptosis in a concentration-dependent manner. Collectively, these findings demonstrate that hydrophobic tagging represents an effective strategy for PARP1 degradation and provides a promising approach for the development of PARP1-targeted anticancer agents.