Dual-target inhibitors of poly (ADP-ribose) polymerase-1 for cancer therapy: Advances, challenges, and opportunities

PARP1 plays a crucial role in DNA damage repair, making it an essential target for cancer therapy. PARP1 inhibitors are widely used to treat BRCA-deficient malignancies, and six PARP inhibitors have been approved for clinical use. However, excluding the great clinical success of PARP inhibitors, the concomitant toxicity, drug resistance, and limited scope of application restrict their clinical efficacy. To find solutions to these problems, dual-target inhibitors have shown great potential. In recent years, several studies have linked PAPR1 to other primary cancer targets. Many dual-target inhibitors have been developed using structural fusion, linkage, or library construction methods, overcoming the defects of many single-target inhibitors of PARP1 and achieving great success in clinical cancer therapy. This review summarizes the advance of dual-target PARP1 inhibitors in recent years, focusing on their structural optimization process, structure-activity relationships (SARs), and in vitro or in vivo analysis results.