Poly(ADP-ribose) polymerase-1 (PARP1)-based dual inhibitors targeting cancer synthetic lethality (2022-present): advances and perspectives

Poly(ADP-ribose) polymerase 1 (PARP1), a critical enzyme in DNA damage repair (DDR) and genome stability maintenance, has emerged as a pivotal therapeutic target in oncology. PARP1 inhibitors (PARPi) exploit synthetic lethality to selectively target homologous recombination repair (HRR)-deficient cancer cells, revolutionizing treatment for patients with breast cancer susceptibility gene 1/2 (BRCA1/2) mutations and other DNA repair defects. However, monotherapy resistance and limited efficacy in broader patient populations necessitate innovative strategies. Recent advances highlight the promise of dual-targeting inhibitors that simultaneously inhibit PARP1 and additional oncogenic drivers (e.g. GFR, CDK, NRP1, Polθ, ALR2, Ras or FTase) to amplify antitumor effects and overcome resistance mechanisms. This review comprehensively examines dual inhibitors relevant to PARP1 in literature not covered in the last review, analyzing their design rationales, structure-activity relationships (SARs), pharmacological activities and synthetic pathways, and more. Furthermore, the challenges in balancing dual inhibitors' potency, in obtaining optimal pharmacokinetics, and in minimizing off-target effects also were discussed. By integrating mechanistic insights with drug discovery trends, this work provides a roadmap for developing next-generation PARP1-based therapies, offering strategic guidance to enhance therapeutic outcomes and expand clinical applicability in heterogeneous malignancies.