From Design to Synergy: Triazine–Triazole Hybrids as Anti-Breast Cancer Leads Targeting Survival and Invasion Pathways for Augmenting Lapatinib Efficacy

Background/Objectives: Breast cancer is the most common cancer diagnosed and the leading cause of cancer-related deaths among women, ranking fourth overall in both sexes. Its treatment is difficult due to drug resistance and side effects from conventional therapies. Developing multitargeted agents and combination approaches offer a promising way to overcome these challenges. This study details the design and testing of new triazole–triazine hybrids as potential anti-breast cancer drugs, exploring their use in combination with lapatinib to enhance its efficacy in breast cancer. Methods: Sixteen triazine–triazole hybrid compounds with amide and ureido linkers were synthesized via click and coupling protocols and tested for their cytotoxic effects on MCF-7 cells using an MTT assay. The most effective compound was evaluated for its inhibitory effect against AXL using an ADP-Glo™ kinase assay, then examined in combination with lapatinib on cellular and molecular levels. In vitro experiments included chemoinvasion assays for metastasis, flow-cytometric analysis of apoptosis, and ELISA to evaluate the molecular mechanisms of promising hits. Molecular docking studies were conducted to simulate the potential target–hit interactions and predict the plausible structural determinants of activity, paving the way for further lead optimization. Results: Compound 6e demonstrated the highest activity (IC50 = 24.58 μM) and good selectivity (SI = 7.87). The combination therapy showed a synergistic effect and increased tumor sensitivity to lapatinib. Biological tests indicated inhibition of the AXL enzyme, downregulation of key pathways (AKT, NF-κB, STAT3, ERK), decreased levels of VEGF, MMP9, and cyclin D1, and increased caspase-3 activity, suggesting apoptosis, which was strengthened by the flow-cytometric analysis findings. Docking results supported multitarget interactions. Conclusions: Compound 6e is a promising multitarget anti-breast cancer candidate with synergistic potential in combination with lapatinib, warranting further in vivo studies.