InhibitWin duo: Rational design and structural insights into dual PARP/HDAC inhibitors for synergistic DNA repair disruption and epigenetic modulation.

Cancer persists as a major health burden, fueled not only by genetic mutations but also by profound epigenetic instability that rewires transcriptional programs and DNA repair networks. Among the most intensively studied epigenetic regulators are histone deacetylases (HDACs) and poly (ADP-ribose) polymerases (PARPs), whose dysregulation fosters genomic instability, unchecked proliferation, and therapeutic resistance. Pharmacological inhibition of HDACs or PARPs alone has achieved meaningful advances, yet intrinsic and acquired resistance, limited tumor selectivity, and relapse remain formidable barriers to durable efficacy. To address these challenges, attention has shifted toward rational combination strategies and, more recently, to the development of dual inhibitors. By integrating key pharmacophoric features from both HDAC and PARP inhibitors, these hybrids are designed to achieve balanced target engagement within a single scaffold, thereby maximizing synergy while reducing pharmacokinetic complexity. Mechanistically, dual blockade disrupts DNA repair fidelity, induces chromatin relaxation, and amplifies apoptotic signaling, thereby producing antitumor effects that exceed those of monotherapy. While this paradigm offers substantial promise, it is not without limitations, including potential off-target toxicity, challenges in optimizing linker chemistry, and the need for precise structure-activity relationship (SAR) refinement. This review consolidates structural, mechanistic, and SAR insights, emphasizing how dual HDAC/PARP inhibition represents a next-generation therapeutic strategy poised to overcome resistance and broaden the spectrum of effective cancer interventions.