Dual HDAC/PI3K inhibitors as a potential and emerging cancer therapy: a review

Cancer continues to cause a major global health challenge, largely because of the heterogeneity of molecular changes that allow cancer cells to grow uncontrollably and evade therapy. The various pathways implicated include HDACs and PI3Ks, which are key epigenetic regulators and intracellular signaling, as well as critical regulators of cell survival and proliferation. Once dysregulated, these pathways contribute to tumor initiation, disease progression, and resistance to currently used treatments. This review presents the biological roles, types, cellular localization, functional diversity, and roles in cancer progression of HDAC and PI3K family members. Further, discussed on the chemistry and SAR of FDA-approved HDAC, PI3K, and dual inhibitors with a special emphasis on the nature of the pharmacophore that affects potency, selectivity, and therapeutic activity. The review focuses on dual HDAC/PI3K inhibition as a single approach to simultaneously inhibit epigenetic regulation and pro-survival signaling in cancer cells. Dual inhibitors, such as CUDC-907 and BEBT-908, and their potential effectiveness in cytogenetic cancers and solid tumors; issues related to clinical trials; and future directions to enhance therapeutic outcomes are discussed. Currently, dual HDAC/PI3K inhibitors are an exciting next-generation anticancer agent that addresses the major drawbacks of existing therapies.