Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors

Poly(ADP-ribose) polymerase (PARP) inhibitors constitute a significant class of targeted anticancer therapies that leverage the principle of synthetic lethality in tumours deficient in homologous recombination (HR) repair. Although these agents have shown clinical efficacy in treating HR-deficient tumours, their wider application has been limited by challenges including the emergence of drug resistance, dependency on HR deficiency phenotypes, and related hematological toxicity. To mitigate these limitations, dual-target PARP inhibitors have emerged as a promising therapeutic strategy, simultaneously modulating PARP and synergistic pathways within a single molecular entity. This approach effectively circumvents the pharmacokinetic complexities and cumulative toxicity associated with multi-drug regimens, while simultaneously enhancing therapeutic efficacy through complementary mechanisms. This review highlights recent progress in PARP-based dual inhibitors, focusing on target selection, structure-activity relationships, synergistic antitumor mechanisms, and future research directions. It combines preclinical and clinical insights to guide the development of next-generation PARP dual-target inhibitors with improved efficacy and safety.