Emerging roles of PARP-1 driven dual inhibitors in cancer therapy: SAR-guided strategies and synthetic lethality

Poly (ADP-ribose) polymerase-1 (PARP-1) plays an important role in DNA damage repair and preservation of genomic integrity, making it promising target in oncology. PARP-1 inhibitors (PARP-1i) employ synthetic lethality to specifically target cells with deficiency in homologous recombination repair, such as those with BRCA1/2 mutation and other DNA impairments. Although PARP-1 inhibitors have shown clinical success, challenges like acquired resistance and limited efficacy are still matters of concern. Increasing evidence supports the potential of dual-targeting inhibitors that target PARP-1 along with other oncogenic drivers (e.g. HDAC, EGFR, and CDK) to amplify anti-proliferative activity and surmount resistance mechanism. This review comprehensively provides in-depth investigation of dual inhibitors in context to PARP-1, evaluating their design rationale, structure activity relationship (SARs), pharmacological properties, synthetic scheme, and more. By combining mechanistic insights with drug discovery, this work aims to create a road map for generating next-generation PARP-1 inhibitors, providing strategic recommendations in order to improve therapeutic efficacy and broaden clinical applicability across diverse cancer types.