Gefitinib-Tamoxifen Hybrid Ligands as Potent Agents against Triple-Negative Breast Cancer

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Current cancer therapies face challenges including limited efficacy, high toxicity, and drug resistance.
• Anticancer drug conjugates offer a potential strategy to overcome these limitations by targeting multiple pathways simultaneously.
• Dual-targeting agents may provide pharmacokinetic advantages and reduce drug-drug interactions compared to combination therapies.

Purpose of the Study:

• To design and synthesize novel hybrid anticancer agents by covalently linking ER antagonists (tamoxifen/endoxifen) with an EGFR inhibitor (gefitinib).
• To evaluate the dual ER antagonist and EGFR inhibitory activities of these novel drug conjugates.
• To assess the anti-cancer efficacy of the most potent analogues in various breast cancer cell lines, including triple-negative breast cancer (TNBC).

Main Methods:

• Synthesis of novel tamoxifen/endoxifen-gefitinib hybrid molecules via covalent linkage.
• In vitro evaluation of ER antagonist activity and EGFR inhibition.
• Cellular viability assays using multiple breast cancer cell lines (MCF7, MDA-MB-231, MDA-MB-468, BT-549).

Main Results:

• Synthesized hybrid ligands effectively retained both ER antagonist activity and EGFR inhibition.
• The most potent analogues demonstrated single-digit nanomolar activity against both targets.
• Amide-linked endoxifen-gefitinib conjugates (17b, 17c) exhibited superior anti-cancer activity in cellular viability assays.
• Compounds 17b and 17c showed nanomolar IC50 values (380 nM - 970 nM) in TNBC cells, outperforming control compounds and combinations.

Conclusions:

• Covalent conjugation of tamoxifen/endoxifen with gefitinib yields potent dual-targeting anticancer agents.
• The endoxifen-gefitinib conjugates 17b and 17c demonstrate significant anti-cancer activity, particularly in TNBC cells.
• These novel drug conjugates represent a promising strategy for overcoming limitations of current breast cancer treatments.