Selective degradation of PARP2 by PROTACs via recruiting DCAF16 for triple-negative breast cancer

Triple negative breast cancer (TNBC) is a complex and heterogeneous neoplasm, and till now no effective therapies are available. PARP inhibitors, which target DNA repair, are lethal to those cells that have impaired homologous recombination (HR) pathway. So, PARP inhibitors might exert promising results in the treatment of BRCA-mutated TNBC, but show compromised effect to those wild-type TNBC. Herein, we describe a novel PROTACs C8, which was obtained by conjugating PARP1/2 inhibitor Olaparib to KB02, can induce potent and specific degradation of PARP2 by recruiting DCAF16 E3 ligase for treatment of wild-type TNBC. Moreover, C8 exhibits therapeutic potential in TNBC cell lines MDA-MB-231 both in vitro and in vivo. These studies demonstrated that the DCAF16 E3 ligases can be used in PARP2 PROTACs design, and C8, as a novel PARP2 selective DCAF16 based PROTACs, might be a promising lead compound for the treatment of BRCA-wild-type TNBC.