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

## TL;DR

This paper reviews multitarget inhibitors that block both PI3K and HDAC enzymes, which could lead to better cancer treatments.

## Contribution

The paper provides a critical overview of recent dual PI3K/HDAC inhibitors and outlines design principles for future drug development.

## Key findings

- Dual inhibition of PI3K and HDAC shows synergistic antitumor effects in cancer cells.
- Fimepinostat is the first clinically tested multitarget inhibitor with balanced activity against both targets.
- Structural diversity and activity profiles of multitarget inhibitors are analyzed to guide future drug design.

## Abstract

Phosphatidylinositol-3-kinases (PI3Ks) constitute an important validated therapeutic class involved in crucial cellular processes, and their dysregulation is associated with cancer initiation and progression. Nonetheless, intrinsic and acquired resistance mechanisms associated with PI3K pathway modulation have underscored the need for alternative therapeutic strategies. In this context, recent studies have shown that simultaneous inhibition of PI3K and histone deacetylases (HDAC) promotes synergistic antitumor effects in different cancer cell lines. HDACs are validated epigenetic targets that are extensively explored in clinical practice and have a pharmacophore with versatility for structural modifications, which facilitates the design of multitarget inhibitors. This review examines the rational design and synthetic evolution of dual PI3K/HDAC inhibitors, an area catalyzed by the development of fimepinostat, the first clinically evaluated agent exhibiting potent and balanced inhibition of both targets. We provide a critical overview of PI3K/HDAC multitarget inhibitors reported in recent years that have progressed to preclinical or clinical investigation, discussing the structural frameworks employed, medicinal chemistry strategies adopted, and structure–activity relationships established. Particular attention is given to advantageous molecular features as well as challenges related to toxicity, pharmacokinetic behavior, and pharmacodynamic modulation. From this comprehensive analysis, we outline key considerations and emerging design principles that may inform the next generation of PI3K/HDAC multitarget drug candidates. Insights derived from the diversity of chemical scaffolds, activity profiles, and selectivity patterns described herein may support the development of innovative therapeutic agents capable of overcoming current limitations in anticancer treatment.