Potent, Gut-Restricted Inhibitors of Divalent Metal Transporter 1: Preclinical Efficacy against Iron Overload and Safety EvaluationS

Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of nonheme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemo-chromatosis or b-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench as-say to identify human DMT1 inhibitors. Dimeric compounds were made to generate more potent compounds with low systemic ex-posure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits di-etary nonheme iron uptake in both rats and pigs yet has negligible systemic exposure. Efficacy is maintained for >2 weeks in a rat subchronic dosing assay. Doses that lowered iron content in the spleen and liver by >50% had no effect on the tissue content of other divalent cations except for cobalt. XEN602 represents a powerful pharmacological tool for understanding the physiologic function of DMT1 in the gut.