Design, Synthesis, and Biological Evaluation of Novel Triazine-Based Dual Histone Deacetylase/phosphatidylinositol 3-kinase Inhibitors for Breast Cancer Therapy.

Breast cancer is the most frequently diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. Triple-negative breast cancer (TNBC) poses a major clinical challenge due to its aggressive nature, limited therapeutic options, and high propensity for drug resistance. Dysregulation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR and histone deacetylase (HDAC) signaling pathways has been implicated in TNBC progression and therapeutic resistance, highlighting their potential as combinatorial targets. In this study, we report the design, synthesis, and biological evaluation of a novel series of triazine-based multitarget inhibitors aimed at the dual inhibition of PI3K and HDAC. Among the synthesized compounds, 5b and 5f demonstrated the most promising profiles, exhibiting low nanomolar IC50 values against HDAC6 (2.33 and 6.02 nM) and PI3Kα (17.5 and 236 nM), respectively. Both compounds reduced cell viability in breast cancer cell lines, with IC50 values below 5 µM in MDA-MB-231 cells. Western blot analysis confirmed inhibition of HDAC and PI3K signaling in treated cells. Molecular docking and dynamics simulations further revealed stable binding modes and favorable interactions within the active sites of both targets. Overall, 5b and 5f represent promising lead candidates for further optimization toward the development of novel dual HDAC/PI3K inhibitors with potential application in TNBC therapy, as evaluated in TNBC-relevant models.