Design and synthesis of the first PARP1 and PRMT5 dual inhibitors for the treatment of breast cancer.

Poly(ADP-ribose) polymerase 1 (PARP1) is a key factor responsible for repairing DNA single-strand breaks and maintaining genomic stability. PARP1 inhibitors have achieved remarkable therapeutic efficacy in the treatment of BRCA-mutant breast cancer. However, only a small proportion of breast cancer patients carry BRCA mutations, which limits the indication scope of such agents. Recent studies have demonstrated that protein arginine methyltransferase 5 (PRMT5) inhibitors can enhance the sensitivity of BRCA wild-type tumor cells to PARP1 inhibitors by suppressing the DNA homologous recombination (HR) pathway. In this study, a series of novel PARP1/PRMT5 dual inhibitors were designed and synthesized for the first time. Among them, compound 8I exerted potent inhibitory activity against both PARP1 and PRMT5, and displayed excellent antiproliferative effects on both BRCA wild-type and BRCA-mutant breast cancer cells. Further mechanistic studies verified that 8I could inhibit HR function by down-regulating the expression of BRCA1, BRCA2 and RAD51, thereby triggering enhanced DNA damage and cell apoptosis. Notably, in the BRCA wild-type MDA-MB-231 xenograft tumor model, compound 8I exhibited more potent in vivo antitumor activity than single-agent treatment with the PARP1 inhibitor Olaparib or the PRMT5 inhibitor GSK3326595, and displayed efficacy comparable to the combination of the two agents. In conclusion, this study established a new class of PARP1/PRMT5 dual inhibitors with prominent synergistic antitumor effects, which hold potential for the treatment of breast cancer.