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

Abstract

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 Zn 2+ 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 N 2 -acyl-2 aminoimidazole core. Combination treatment with ZnSO 4 strongly potentiated ZNA's cancer specific cell death mechanism, an effect that was not observed with other transition metals. We show that Zn 2+ -dyshomeostasis induced by ZNA is unique and markedly more selective than other known Zn 2+ 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 N 2 -acyl-2aminoimidazole core of ZNA represents a powerful chemotype to induce cell death in cancer cells concurrently with a disruption in zinc homeostasis.

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

“…The bioinorganic community has explored the use of coordination and organometallic compounds as inhibitors or as auxiliary groups to augment existing organic moieties, [17][18][19][20][21][22] and some of these metal-containing inhibitors having entered clinical trials, such as ferroquine. 23,24 A few uses of organometallic groups to augment existing organic inhibitors have produced spectacular results, including highly selective and active kinase inhibitors.…”

Targeting zinc metalloenzymes in coronavirus disease 2019

“…Targeting metal homeostasis with the aid of chelators or ionophores has been suggested as a therapeutic strategy for a variety of diseases, for example, cancer (Ding & Lind, 2009; Vaden et al, 2019), diseases of the CNS (Doboszewska et al, 2017; Doboszewska et al, 2019; Weekley & He, 2017) and infectious diseases, such as malaria (Bharti, Singal, Raza, Ghosh, & Nag, 2019). An important fact is that there are ongoing clinical trials in which metal‐binding compounds are being tested because of their influence on metal homeostasis.…”

Strategies of Perturbing Ion Homeostasis for Cancer Therapy

“…[4] Recently, various approaches for perturbing ion homeostasis have been intensively investigated to develop new and effective anticancer DOI: 10.1002/adtp.202100189 agents ranging from prevalent ions to trace metal ions. [4,5] Various ion homeostasisperturbing agents, such as small moleculebased ionophores [6][7][8][9][10][11][12] or chelators, [13][14][15][16] metal ion nanoparticles (NPs), [17][18][19][20][21][22] and peptide-based ionophores, [23,24] can trigger programmed cell death and also boost antitumor immunity by activating or deactivating specific signaling pathways (Figure 1). Prevalent ions such as chloride, calcium, and potassium have been attractive targets to disturb ion homeostasis.…”

“…Moreover, metal ion homeostasis provides new insights for cancer therapy. [11,12,[25][26][27][28] Two main approaches have been developed to promote programmed cell death: overload or chelation of metal ions. For metal accumulation in cancers, metal NPs and metal ionophores have been widely used to stimulate metal overload in cells, thereby activating programmed cell death.…”