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Beyond PARP-HDAC inhibition: mechanistic rationale and medicinal chemistry insights from single to shared-target
Eman M Elkafoury1, Shahenda Mahmoud1, Kamyar Afarinkia2
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tanta University, 31527 Tanta, Egypt.
Abstract:
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.
Insights
Dual Poly(ADP-ribose) polymerase (PARP) and histone deacetylase (HDAC) inhibitors show promise for enhanced cancer therapy by targeting DNA repair and chromatin regulation. This approach aims to improve efficacy and overcome resistance in cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Poly(ADP-ribose) polymerase (PARP) and histone deacetylases (HDACs) are crucial for DNA repair and chromatin regulation, respectively, making them key cancer targets.
- PARP inhibitors are effective in tumors with DNA repair defects, while HDAC inhibitors target epigenetic control of cell proliferation and apoptosis.
- Crosstalk between PARP and HDAC pathways justifies developing dual inhibitors to enhance anti-cancer effects and combat resistance.
Purpose of the Study:
- To review the mechanisms, structures, and applications of PARP and HDAC inhibitors.
- To explore the development and medicinal chemistry rationale of dual PARP-HDAC inhibitors.
- To discuss interconnected therapeutic targets for next-generation multi-target anticancer agents.
Main Methods:
- Comprehensive literature review of PARP inhibitors, HDAC inhibitors, and dual PARP-HDAC inhibitors.
- Analysis of medicinal chemistry strategies for dual inhibitor design, including pharmacophore hybridization and SAR.
- Examination of combined or hybrid strategies with other therapeutic targets.
Main Results:
- PARP and HDAC inhibitors have distinct yet interconnected roles in cancer biology.
- Dual PARP-HDAC inhibitors are being designed using strategies like linker optimization and incorporation of specific binding motifs.
- Several other targets (e.g., tubulin, proteasome, EGFR, VEGFR2, CDKs, topoisomerases, EZH2, BRD4, c-MET) are being explored in conjunction with PARP/HDAC inhibition.
Conclusions:
- Dual PARP-HDAC inhibitors represent a promising strategy to enhance anticancer efficacy and overcome resistance.
- Understanding the interplay between PARP, HDAC, and other signaling pathways is crucial for developing effective multi-target cancer therapies.
- Further research into next-generation agents targeting multiple pathways could lead to improved patient outcomes.
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