The ABCG2 transporter in protoporphyrin IX disposition: from toxicity to therapy

原卟啉 IX 处置中的 ABCG2 转运蛋白：从毒性到治疗

• 批准号: 10598606
• 负责人: Xiaochao Ma
• 金额: $ 34.06万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598606
• 关键词: ABCG2 gene; Attenuated; Bile fluid; Binding Proteins; Bone Marrow; Chemicals; Cholestasis; Clinical; Data; Drug Design; Drug Kinetics; Drug or chemical Tissue Distribution; Drug usage; Enzymes; Erythrocytes; Erythropoietic Protoporphyria; Evaluation; Excretory function; Genetic Diseases; Genetic Engineering; Heme; Hepatobiliary; Hepatocyte; Hepatotoxicity; Hydrophobicity; Life; Link; Liver; Liver Failure; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Pathway interactions; Patients; Phototoxicity; Plasma; Play; Prevention; Pump; Role; Safety; Skin; Specificity; System; Testing; Therapeutic; Toxic Environmental Substances; Toxic effect; Work; analog; bile duct; biliary tract; common symptom; cytotoxicity; efficacy evaluation; ferrochelatase; heme biosynthesis; hydrophilicity; improved; in vivo; inhibitor; liver injury; loss of function mutation; metabolic profile; mouse model; novel; novel strategies; novel therapeutics; prevent; protoporphyrin IX; public health relevance; uptake

ABSTRACT Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are two genetic diseases characterized by protoporphyrin IX (PPIX)-mediated phototoxicity and hepatotoxicity, and there is no cure. The objective of this project is to develop a mechanism-based strategy to manage PPIX-mediated toxicities. Our preliminary studies found that ABCG2, the efflux transporter of PPIX, plays an essential role in PPIX-mediated toxicities, and deficiency of ABCG2 abolishes such toxicities. Our further studies found that ABCG2 deficiency modulates PPIX distribution and metabolism. Based on these results, we hypothesize that suppression of ABCG2 will attenuate PPIX-mediated toxicities by modulating PPIX disposition. To test our hypothesis, we propose the following specific aims: (1) to develop ABCG2 inhibitors for the management of PPIX-mediated toxicities; (2) to determine the efficacy, safety, and mechanisms of action of these novel ABCG2 inhibitors for the prevention of PPIX-mediated phototoxicity; and (3) to determine the efficacy, safety, and mechanisms of action of ABCG2 inhibitors for the treatment of PPIX-mediated hepatotoxicity. We have successfully synthesized 28 ABCG2 inhibitors, and our preliminary data are promising because several of the tested candidates showed strong ABCG2 inhibitory activity and great efficacy against PPIX-mediated toxicities. In summary, this project will explore the therapeutic potential of ABCG2 inhibitors for the management of PPIX-mediated phototoxicity and hepatotoxicity. We will also illustrate the mechanisms by which suppression of ABCG2 attenuates PPIX- mediated toxicities. Genetically engineered ABCG2 and EPP mouse models together with ABCG2 inhibitors will be used in our proposed work. The results from this project will provide a novel strategy for the management of EPP and XLP.

摘要 红细胞生成性原红细胞增多症(EPP)和X连锁原红细胞增多症(XLP)是两种遗传病 以原卟啉IX(PPIX)介导的光毒性和肝毒性为特征，目前尚无治愈方法。 该项目的目标是开发一种基于机制的策略来管理PPIX中介 毒物。我们的初步研究发现，PPIX的外流转运体ABCG2在 在PPIX介导的毒性中起作用，缺乏ABCG2可消除这种毒性。我们的进一步研究 发现ABCG2缺乏调节PPIX的分布和代谢。基于这些结果，我们 假设ABCG2的抑制将通过调节PPIX来减弱PPIX介导的毒性 性情。为了验证我们的假设，我们提出了以下具体目标：(1)开发ABCG2 用于管理PPIX介导的毒性的抑制剂；(2)确定其有效性、安全性和 这些新型ABCG2抑制剂预防PPIX介导的光毒性的作用机制； 以及(3)确定ABCG2抑制剂的疗效、安全性和作用机制 PPIX介导的肝毒性。我们已经成功合成了28个ABCG2抑制剂，我们的 初步数据是有希望的，因为几个被测试的候选者显示出很强的ABCG2抑制作用 对PPIX介导的毒性具有很强的活性和显著的疗效。总而言之，这个项目将探索 ABCG2抑制剂治疗PPIX介导的光毒性和 肝脏毒性。我们还将说明抑制ABCG2减弱PPIX的机制。 中介毒性。基因工程ABCG2和EPP小鼠模型及ABCG2 在我们提议的工作中将使用抑制剂。该项目的成果将提供一种新的战略 EPP和XLP的管理。