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

Anticancer drug conjugates may benefit
from simultaneous action
at two targets potentially overcoming the drawbacks of current cancer
treatment, such as insufficient efficacy, high toxicity, and development
of resistance. Compared to a combination of two single-target drugs,
they may offer an advantage of pharmacokinetic simplicity and fewer
drug–drug interactions. Here, we report a series of compounds
connecting tamoxifen or endoxifen with the EGFR-inhibitor gefitinib
via a covalent linkage. These hybrid ligands retain both ER antagonist
activity and EGFR inhibition. The most potent analogues exhibited
single-digit nanomolar activities at both targets. The amide-linked
endoxifen-gefitinib drug conjugates 17b and 17c demonstrated the most favorable anti-cancer profile in cellular
viability assays on MCF7, MDA-MB-231, MDA-MB-468, and BT-549 breast
cancer cells. Most importantly, in TNBC cells 17b and 17c displayed nanomolar IC50-values (380 nM –
970 nM) and were superior in their anti-cancer activity compared to
their control compounds and combinations thereof.