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Phosphatidylinositol-3-Kinase (PI3K) and Histone Deacetylase (HDAC) Multitarget Inhibitors: An Update on Clinical and

Alef D S Lima1,2, Lídia M Lima1,2

  • 1Laboratory for the Evaluation and Synthesis of Bioactive Substances (LASSBio®), National Institute of Science and Technology for Drugs and Medicines (INCT-INOFAR), Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.

Pharmaceuticals (Basel, Switzerland)
|January 28, 2026
PubMed

Insights

Dual inhibition of Phosphatidylinositol-3-kinases (PI3K) and histone deacetylases (HDAC) offers synergistic anticancer effects. This review explores the design of novel dual PI3K/HDAC inhibitors to overcome drug resistance in cancer therapy.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Epigenetics

Background:

  • Dysregulated Phosphatidylinositol-3-kinases (PI3K) drive cancer initiation and progression.
  • Resistance to PI3K pathway inhibitors necessitates alternative therapeutic strategies.
  • Histone deacetylases (HDAC) are validated epigenetic targets with potential for multitarget inhibitor design.

Purpose of the Study:

  • To review the rational design and synthetic evolution of dual PI3K/HDAC inhibitors.
  • To critically overview recent preclinical and clinical PI3K/HDAC multitarget inhibitors.
  • To outline design principles for next-generation PI3K/HDAC drug candidates.

Main Methods:

  • Analysis of structural frameworks and medicinal chemistry strategies for dual inhibitors.
  • Evaluation of structure-activity relationships (SAR) for PI3K/HDAC inhibitors.
  • Review of preclinical and clinical data for fimepinostat and other dual agents.

Main Results:

  • Simultaneous PI3K and HDAC inhibition demonstrates synergistic antitumor effects.
  • Fimepinostat is the first clinically evaluated dual PI3K/HDAC inhibitor.
  • Diverse chemical scaffolds and activity profiles exist for PI3K/HDAC inhibitors.

Conclusions:

  • Dual PI3K/HDAC inhibitors represent a promising therapeutic strategy for cancer.
  • Understanding molecular features, toxicity, and pharmacokinetics is crucial for drug development.
  • Further research into PI3K/HDAC multitarget agents may yield innovative anticancer therapies.
Keywords:
HDAC and PI3K inhibitioncancermultitarget-directed ligands

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