A comprehensive review of the mechanism and application prospect of PARP dual-target inhibitors in tumor treatment.

Abstract

Although the inhibitors targeting PARP are successfully applied in the clinical treatment of tumors, the further application of PARP inhibitors is limited by reasons such as multi-drug resistance, the DNA replication fork function recovery and relatively low proportion of BRCA1/2-mutant tumors. There have been relevant clinical studies focusing on the combination therapy of PARP inhibitors, and an increasing number of studies have shown that PARP has the potential for synergistic treatment with targets such as HDAC, PI3K, and EZH2 etc. This review summarized the synergistic therapeutic mechanisms of PARP and other anti-tumor targets and the research progress of corresponding dual-target inhibitors in recent years, with the aim of providing inspiration for the subsequent drug development. Compared to previous similar reviews, this review covered the latest research advances, offered a broader range of targets including DNA damage repair, epigenetics, and kinases, which provided detailed insights into synergistic mechanisms, summarized structure-activity relationships, and included molecular docking analyses.