Divalent metal transporter 1 (DMT1) cotransports ferrous iron and protons and is the primary mechanism for uptake of non-heme iron by enterocytes. Inhibitors are potentially useful as therapeutic agents to treat iron overload disorders such as hereditary hemochromatosis or β-thalassemia intermedia, provided that inhibition can be restricted to the duodenum. We used a calcein quench assay to identify human DMT1 (hDMT1) inhibitors. Dimeric constructs were made to generate more potent compounds with low systemic exposure. Direct block of DMT1 was confirmed by voltage clamp measurements. The lead compound, XEN602, strongly inhibits dietary 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 physiological function of DMT1.

中文翻译：

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二价金属转运蛋白 1 (DMT1) 的强效、肠道限制性抑制剂：抗铁过载的临床前疗效和安全性评估

二价金属转运蛋白 1 (DMT1) cotransports 亚铁和质子，是肠细胞摄取非血红素铁的主要机制。抑制剂可用作治疗剂以治疗铁过载疾病，例如遗传性血色素沉着症或中间型β-地中海贫血，前提是抑制作用可以限制在十二指肠。我们使用钙黄绿素淬灭法来鉴定人 DMT1 (hDMT1) 抑制剂。制造二聚体构建体以产生具有低全身暴露的更有效的化合物。DMT1 的直接阻断通过电压钳测量得到证实。先导化合物 XEN602 强烈抑制大鼠和猪的膳食铁摄取，但全身暴露量可忽略不计。在大鼠亚慢性给药试验中功效维持>2周。降低脾脏和肝脏中铁含量的剂量 > 50% 对除钴以外的其他二价阳离子的组织含量没有影响。XEN602 是了解 DMT1 生理功能的强大药理学工具。