Ferristatin: A New Small Molecule Inhibitor of Iron Transport

描述（由申请人提供）：本申请涉及广泛的挑战领域15，转化科学，以及具体的挑战主题15- dk -103：将NIDDK疾病发病机制中的新分子和途径的发现转化为潜在的治疗，诊断或研究工具。铁转运的生物化学原理还没有完全了解。尽管缺铁是美国最普遍的营养问题，但每20个白种人中就有1个携带HFE等位基因变异，这种变异会促进对铁超载的易感性。因此，有必要为铁缺乏和铁超载的疾病开发新的治疗策略。通过高通量荧光筛选，我们的实验室最近发现铁司他汀（NSC306711）抑制维持体内平衡的两个主要铁转运过程：二价金属转运蛋白1 （DMT1）介导的铁摄取和非转铁蛋白结合铁摄取。氯唑黑（NSC8679）具有相似的结构和相当的转运作用。本项目将进一步研究这两种小分子和相关化合物在体内对a)肠道铁摄取到血管的药代动力学的影响；B)红细胞铁摄取和肝脏非转铁蛋白结合铁摄取；c)铁体内平衡和过载逆转。这些努力将进一步阐明调节铁稳态的生化过程，并为开发针对贫血和血色素沉着症的靶向小分子疗法提供基础。

DESCRIPTION (provided by applicant): This application addresses the broad Challenge Area 15, Translational Sciences, and specific challenge topic 15-DK-103: Translate discovery of new molecules and pathways in pathogenesis of NIDDK diseases into potential therapies, diagnostics, or research tools. The biochemistry of iron transport is not thoroughly understood. Although iron deficiency is the most prevalent nutritional problem in the U.S., 1 in 20 Caucasians carry genetic variants of HFE alleles that promote susceptibility to iron overload. Thus, there is a need to develop new therapeutic strategies for diseases of both iron deficiency and overload. Through high-throughput fluorescence-based screening, our lab recently discovered that ferristatin (NSC306711) inhibits both of the major iron transport processes that maintain homeostasis: transferrin- mediated iron uptake and non-transferrin-bound iron uptake by Divalent Metal Transporter 1 (DMT1). Chlorazol black (NSC8679) is structurally similar and has comparable effects on transport. This project will further investigate the impact of these two small molecules and related compounds in vivo, on a) pharmacokinetics of intestinal iron uptake to the vasculature; b) iron uptake into erythroid cells and hepatic non-transferrin bound iron uptake; and c) iron homeostasis and reversal of overload. These efforts will further our goals to elucidate the biochemical processes regulating iron homeostasis, and to provide a foundation for the development of targeted small-molecule therapies for states of anemia and hemochromatosis. PUBLIC HEALTH RELEVANCE: Iron deficiency remains the most prevalent nutritional problem in our country, yet recent identification of the gene responsible for hereditary hemochromatosis indicates that 1 in 20 Caucasians carry the defective allele and thus 1 in 400 may be susceptible to iron overload. Increased knowledge about the transport factors and how they protect against iron deficiency and overload is essential to more broadly address these significant health problems.