Chemical Biology of IRP1-HIF2a Signaling

IRP1-HIF2a 信号转导的化学生物学

基本信息

批准号：
10213663
负责人：
Othon Iliopoulos
金额：
$ 60.49万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213663
关键词：
Animal Model Behavior Binding Biological Assay Biology Cancer Model Carbon Cell Line Cells Cellular Metabolic Process Chemicals Clear cell renal cell carcinoma Disease Dissection Dose Drug Kinetics Embryo Evaluation Genetic Glioblastoma Growth Human Hypoxia Hypoxia Inducible Factor Inflammation Iron Regulatory Protein 1 Lead Lesion Link Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of prostate Metabolism Modeling Molecular Molecular Target Mus Mutation Nature Neoplasm Metastasis Nodal Nude Mice Pharmaceutical Chemistry Pharmacology Post-Translational Protein Processing Pre-Clinical Model Prognosis Property Proteins Regulation Renal Cell Carcinoma Reporter Schedule Series Signal Transduction Specificity Stem Cell Development Structure-Activity Relationship Testing Transcription Factor AP-1 Transgenic Animals Transgenic Mice Translations VHL mutation Validation Vertebrates Von Hippel-Lindau Syndrome Xenograft procedure Zebrafish analog angiogenesis bHLH-PAS factor HLF base efficacy testing experimental study human disease hypoxia inducible factor 1 improved in vivo inhibitor/antagonist insight knock-down mutant novel preclinical study small molecule therapeutic target tool transcription factor tumor tumor hypoxia tumor metabolism

项目摘要

ABSTRACT HIF2a is a transcription factor induced by hypoxia and tumor associated mutations. HIF2a is a nodal regulator of cancer angiogenesis and cancer metabolism, stem cell development and inflammation and it is validated as a therapeutic target in von Hippel-Lindau (VHL)-deficient clear cell renal cell carcinoma (ccRCC). HIF2a had also been implicated in other diseases, beyond ccRCC, such as glioblastoma and prostate cancer. We identified specific HIF2a inhibitors and, by using them as chemical biology tools, we discovered that these small molecules activate Iron Regulatory Protein 1 (IRP1) to suppress HIF2a translation. In this application we propose to validate IRP1 as a target for HIF2a inhibition in xenograft and transgenic animal models of ccRCC and VHL disease. In addition, we propose to gain further insights into the complexity of IRP1-HIF signaling by identifying the direct protein target of HIF2a inhibitors. Finally, we propose to synthesize a series of derivatives of HIF2a inhibitors to further improve their potency and physicochemical properties in order to generate compounds suitable for in vivo preclinical studies and/or tools for further in vivo dissection of HIF2a biology.

抽象的 HIF2A是由缺氧和肿瘤相关突变引起的转录因子。 HIF2A是一个癌症血管生成和癌症代谢，干细胞发育和炎症，并在von hippel-lindau（VHL）缺陷中被证明为治疗靶标透明细胞肾细胞癌（CCRCC）。 HIF2A也与其他疾病有关，除CCRCC之外，例如胶质母细胞瘤和前列腺癌。我们确定了特定的HIF2A抑制剂，并通过使用它们作为化学生物学工具，我们发现这些小分子激活铁调节蛋白1（IRP1）以抑制 HIF2A翻译。在此应用中，我们建议验证IRP1作为异种移植物中HIF2A抑制的靶标 CCRCC和VHL疾病的转基因动物模型。此外，我们建议进一步获得通过识别HIF2A的直接蛋白质靶标，可以洞悉IRP1-HIF信号传导的复杂性抑制剂。最后，我们建议合成一系列HIF2A抑制剂的衍生物，以进一步提高其效力和理化特性，以生成合适的化合物用于体内临床前研究和/或工具，用于进一步的HIF2A生物学体内解剖。