A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A

We
present data demonstrating the natural product mimic, zinaamidole
A (ZNA), is a modulator of metal ion homeostasis causing cancer-selective
cell death by specifically inducing cellular Zn2+-uptake
in transformed cells. ZNA’s cancer selectivity was evaluated
using metastatic, patient-derived breast cancer cells, established
human breast cancer cell lines, and three-dimensional organoid models
derived from normal and transformed mouse mammary glands. Structural
analysis of ZNA demonstrated that the compound interacts with zinc
through the N2-acyl-2-aminoimidazole core.
Combination treatment with ZnSO4 strongly potentiated ZNA’s
cancer-specific cell death mechanism, an effect that was not observed
with other transition metals. We show that Zn2+-dyshomeostasis
induced by ZNA is unique and markedly more selective than other known
Zn2+-interacting compounds such as clioquinol. The in vivo bioactivity of ZNA was also assessed and revealed
that tumor-bearing mice treated with ZNA had improved survival outcomes.
Collectively, these data demonstrate that the N2-acyl-2-aminoimidazole core of ZNA represents a powerful chemotype
to induce cell death in cancer cells concurrently with a disruption
in zinc homeostasis.