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

Eman M Elkafoury¹, Tarek F El-Moselhy¹, Mervat H El-Hamamsy¹

¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, Tanta, 31527, Egypt.

European Journal of Medicinal Chemistry

|March 17, 2026

Abstract:

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.

Insights

Dual inhibitors targeting histone deacetylases (HDACs) and poly (ADP-ribose) polymerases (PARPs) offer a promising strategy to overcome cancer resistance. These novel agents enhance antitumor effects beyond monotherapy, addressing key challenges in cancer treatment.

Area of Science:

Oncology
Epigenetics
Pharmacology

Background:

Cancer's complexity involves genetic mutations and epigenetic instability, impacting gene expression and DNA repair.
Histone deacetylases (HDACs) and poly (ADP-ribose) polymerases (PARPs) are key epigenetic regulators whose dysregulation drives cancer progression and resistance.
Current HDAC or PARP inhibitors show efficacy but face limitations like resistance, limited tumor selectivity, and relapse.

Purpose of the Study:

To review the structural, mechanistic, and structure-activity relationship (SAR) insights of dual HDAC/PARP inhibitors.
To highlight dual inhibition as a next-generation strategy for overcoming cancer therapeutic resistance.
To explore the potential of dual HDAC/PARP inhibitors in broadening effective cancer interventions.

Main Methods:

Integration of pharmacophoric features from HDAC and PARP inhibitors into single molecular scaffolds.
Analysis of mechanisms including disruption of DNA repair fidelity, chromatin relaxation, and amplified apoptotic signaling.
Consolidation of structural, mechanistic, and SAR data for dual inhibitor development.

Main Results:

Dual HDAC/PARP inhibitors achieve balanced target engagement, maximizing synergy and reducing pharmacokinetic complexity.
Combined blockade demonstrates enhanced antitumor effects compared to monotherapy by disrupting DNA repair and inducing apoptosis.
Development of dual inhibitors represents a rational approach to address limitations of single-target agents.

Conclusions:

Dual HDAC/PARP inhibition is a promising therapeutic strategy for overcoming cancer resistance and improving treatment outcomes.
This approach offers potential for broader application in cancer intervention by tackling multiple oncogenic pathways simultaneously.
Further refinement of linker chemistry and SAR is crucial for optimizing the clinical potential of these dual inhibitors.

Read full analysis

Keywords:

BRCA Cancer DNA damage Dual inhibitors HDAC Hydroxamic acid PARP Phthalazinone ZBG

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