PI3K/HDAC Dual Inhibitors as Potential Anticancer Therapeutics: An Insight Into Design Strategies and Structure Activity Relationships

Cancer therapy faces significant challenges due to the limitations of single‐target agents and the practical complications of combination regimens, including toxicity, drug–drug interactions, and acquired resistance. Simultaneous inhibition of synergistic oncogenic pathways is a promising strategy to overcome these hurdles. The phosphoinositide 3‐kinase (PI3K) and histone deacetylase (HDAC) pathways are critically interconnected in driving tumor proliferation, metastasis, and immune evasion. This review comprehensively assesses the emerging therapeutic paradigm of dual PI3K/HDAC inhibitors as a transformative approach in precision oncology. We highlight the mechanistic synergy between PI3K and HDAC isoforms, detailing their crosstalk in sustaining survival signals and fostering resistance. The design rationale, synthesis, and structure‐activity relationship (SAR) of reported (all papers related to PI3K/HDAC dual inhibitors against cancer; 2020‐25) small‐molecule dual PI3K/HDAC inhibitors are discussed and analyzed. A generalized structural model is derived, identifying four indispensable components: a hinge‐binding heterocyclic core for PI3K affinity, a zinc‐binding group for HDAC inhibition, a flexible 5‐6 carbon linker for optimal positioning, and a bulky aromatic capping group to enhance potency for both targets. This review underscores the potential of dual PI3K/HDAC inhibition and provides a robust structural framework for the future development of optimized isoform‐selective therapeutics for cancer treatment.