Managing Iron Overload: A Gut Check.

Divalent metal transporter 1 (DMT1) is the major importer of ferrous iron at the apical surface of enterocytes in the duodenum. Multiple groups have tried to design specific inhibitors for DMT1 both to study its contributions to iron (and metal ion) homeostasis and to provide a pharmacological means to treat iron overload disorders like hereditary hemochromatosis and thalassemias. This task faces challenges because many tissues express DMT1 and DMT1 transports other metals adding to standard risks in making specific inhibitors. Xenon Pharmaceuticals have published several papers on their efforts. Their latest paper in this issue of the journal culminates their efforts with compounds named XEN601 and XEN602 but implies that these very effective inhibitors have sufficient toxicity for them to halt development. This Viewpoint evaluates their efforts and briefly considers alternative routes to the goal. SIGNIFICANCE STATEMENT: This Viewpoint briefly reviews the paper on inhibitors of DMT1 that appears in this issue of the journal and commends the effort and research utility of those developed by Xenon. The inhibitors have proven to be valuable research tools for studying metal ion homeostasis particularly for iron. If Xenon is ceasing to try to develop them for treatment of iron overload disorders, then new alternatives need to come to the fore.