From Design to Synergy: Triazine-Triazole Hybrids as Anti-Breast Cancer Leads Targeting Survival and Invasion Pathways for Augmenting Lapatinib Efficacy.
10 affiliations
- 1Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
- 2Department of Medicinal Chemistry, College of Pharmacy, Arab Academy for Science, Technology and Maritime Transport, El-Alamein 5060305, Egypt.
- 3Department of Medicinal Chemistry, Faculty of Pharmacy, Minia National University, New Minia 61768, Egypt.
- 4Department of Microbiology and Immunology, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
- 5Pharmacology and Toxicology Department, Faculty of Pharmacy, Damanhour University, Damanhour 22511, Egypt.
- 6Pharmacology and Toxicology Department, Faculty of Pharmacy, Damanhour National University, Damanhour 22511, Egypt.
- 7College of Engineering and Technology, Arab Academy for Science, Technology and Marine Transport, El-Alamein 5060305, Egypt.
- 8Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt.
- 9Department of Medicinal Chemistry, Faculty of Pharmacy, Alamein International University (AIU), El-Alamein 5060310, Egypt.
- 10Chemistry Department, Faculty of Science, Alexandria University, Alexandria 21511, Egypt.
Abstract
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.
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BibTeX
@article{ali2026from,
title = {{From Design to Synergy: Triazine-Triazole Hybrids as Anti-Breast Cancer Leads Targeting Survival and Invasion Pathways for Augmenting Lapatinib Efficacy.}},
author = {Omnia M Ali and Samar Hafez Abbas and Micheal G Shehat and Maged W Helmy and Moustafa H Aly and Mohamed Teleb and Sherine N Khattab and Mohamed Abdel-Aziz},
journal = {Pharmaceuticals (Basel, Switzerland)},
year = {2026},
month = oct,
doi = {10.3390/ph19101656},
url = {https://europepmc.org/article/MED/42943353},
note = {CC BY},
}
RIS
TY - JOUR
TI - From Design to Synergy: Triazine-Triazole Hybrids as Anti-Breast Cancer Leads Targeting Survival and Invasion Pathways for Augmenting Lapatinib Efficacy.
AU - Omnia M Ali
AU - Samar Hafez Abbas
AU - Micheal G Shehat
AU - Maged W Helmy
AU - Moustafa H Aly
AU - Mohamed Teleb
AU - Sherine N Khattab
AU - Mohamed Abdel-Aziz
PY - 2026
DA - 2026/10/20
JO - Pharmaceuticals (Basel, Switzerland)
DO - 10.3390/ph19101656
UR - https://europepmc.org/article/MED/42943353
AB - 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.
SN - 1424-8247
ER -