Discovery of CN0 as a novel proteolysis-targeting chimera (PROTAC) degrader of PARP1 that can activate the cGAS/STING immunity pathway combined with daunorubicin

Poly ADP-ribose polymerase 1 (PARP1) plays an essential role in DNA repair signaling, rendering it an attractive target for cancer treatment. Despite the success of PARP1 inhibitors (PARPis), only a few patients can currently benefit from PARPis. Moreover, drug resistance to PARPis occurs during clinical treatment. Natural and acquired resistance to PARPis has forced us to seek new therapeutic approaches that target PARP1. Here, we synthesized a series of compounds by proteolysis-targeting chimera (PROTAC) technology to directly degrade the PARP1 protein. We found that CN0 (compound 3) with no polyethylene glycol (PEG) linker can degrade the PARP1 protein through the proteasome pathway. More importantly, CN0 could inhibit DNA damage repair, resulting in highly efficient accumulation of cytosolic DNA fragments due to unresolved unrepaired DNA lesions when combined with daunorubicin (DNR). Therefore, CN0 can activate the cyclic GMP-AMP synthase/stimulator of the interferon gene (cGAS/STING) pathway of innate immunity and then spread the resulting inflammatory signals, thereby reshaping the tumor microenvironment, which may eventually enhance T cell killing of tumor cells.