Beyond PARP-HDAC inhibition: mechanistic rationale and medicinal chemistry insights from single to shared-target strategies.

Poly(ADP-ribose) polymerase (PARP) and histone deacetylases (HDACs) are critical regulators of DNA repair and chromatin dynamics, making them important targets in cancer therapy. PARP inhibitors exploit defects in DNA repair pathways, particularly in tumors with homologous recombination deficiency, whereas HDAC inhibitors modulate epigenetic mechanisms that control cell proliferation and apoptosis. Emerging evidence of crosstalk between PARP-mediated DNA repair and HDAC-dependent chromatin regulation provides a strong rationale for the development of dual PARP-HDAC inhibitors as a strategy to enhance anticancer efficacy and overcome therapeutic resistance. This review provides a comprehensive overview of PARP inhibitors and HDAC inhibitors, including their mechanisms of action, structural features, and therapeutic applications. In addition, the progress in the development of dual PARP-HDAC inhibitors is covered, with particular emphasis on the medicinal chemistry rationale underlying their design, including pharmacophore hybridization strategies, structure-activity relationship (SAR) insights, linker optimization, and the incorporation of zinc-binding groups and PARP-binding motifs to achieve balanced dual-target inhibition and improved anticancer activity. Furthermore, the review discusses several shared and interconnected therapeutic targets that have been explored in combination or hybrid strategies with PARP or HDAC inhibition, including tubulin, proteasome, EGFR, VEGFR2, CDKs, topoisomerase I and II, EZH2, BRD4, and c-MET. Understanding these interconnected pathways may facilitate the development of next-generation multitarget anticancer agents with improved efficacy and reduced resistance.