Targeting the core components of the Hsp90 chaperoning machine

瞄准Hsp90陪伴机核心部件

• 批准号: 8344548
• 负责人: Ahmed Chadli
• 金额: $ 24.02万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8344548
• 关键词: 17-(Allylamino)-17-demethoxygeldanamycin; ATP phosphohydrolase; Address; Affect; Apoptosis Inhibitor; Binding; Binding Sites; Biochemical; Biological Assay; Biology; Cancer cell line; Cardiovascular Diseases; Cell Survival; Cells; Chemicals; Client; Clinic; Clinical; Clinical Trials; Collection; Complex; Diabetes Mellitus; Disease; Ensure; Etiology; Glucocorticoid Receptor; Glucocorticoids; Heat shock proteins; Heat-Shock Proteins 90; Heating; Homeostasis; Hop protein; Hormones; Humulus; Immunoprecipitation; In Vitro; Individual; Libraries; Maintenance; Malignant Neoplasms; Measures; Metabolic; Metalloproteases; Molecular Chaperones; Molecular Conformation; Molecular Probes; Molecular Target; N-terminal; Nerve Degeneration; Neurodegenerative Disorders; Nitric Oxide; Oncogenic; Oryctolagus cuniculus; Outcome; Pharmaceutical Preparations; Phase; Phosphotransferases; Physiological; Progesterone; Progesterone Receptors; Protein Isoforms; Proteins; Proteome; Recovery; Reticulocytes; Role; Screening procedure; Signal Pathway; Source; Steroid Receptors; System; Testing; United States National Institutes of Health; Validation; Work; base; cancer cell; cancer therapy; combinatorial; design; drug discovery; experience; genetic regulatory protein; high throughput screening; human disease; inhibitor/antagonist; miniaturize; novel; overexpression; reconstitution; small molecule; therapeutic development; tool; transcription factor

DESCRIPTION (provided by applicant): Molecular chaperones are key players in the maintenance of a healthy proteome and in homeostasis of the cell. Dysregulation in the function of molecular chaperones leads to many metabolic, oncological, neurodegenerative, and cardiovascular diseases. The Hsp90 chaperoning machine, in particular, involves a number of chaperones and co-chaperones that, through a complex network of interactions, ensure the folding and the functionality of many key regulatory proteins. Current information suggests that targeting this machine may have a significant and combinatorial impact on dysfunctional circuitries that underlie human diseases such as cancer and neurodegenerative diseases. Novel small-molecule compounds that target the Hsp90 machine in a selective manner are needed. They will provide tools and molecular probes to further dissect the biology of this machine to better understand its role in disease etiology and progression, and to facilitate the subsequent development of therapeutics against relevant targets. This application aims to develop a high- throughput assay based on progesterone and glucocorticoid receptors, which are physiological clients of Hsp90, and the core components of the Hsp90 chaperoning machine (Hsp90, Hsp70, Hsp40, Hop, and p23). This assay would significantly enhance the discovery of chemical probes that would affect the functional core of the Hsp90 machine. It would also provide the long sought-after screening tool for specific inhibitors of Hsp90 alpha and beta isoforms and facilitate the identification of molecular targets of active compounds. PUBLIC HEALTH RELEVANCE: This project aims to develop a new high-throughput assay to discover novel inhibitors of molecular chaperones, which could eventually be developed as drugs against cancer and other human diseases.

描述(由申请人提供)：分子伴侣是维持健康蛋白质组和细胞内稳态的关键角色。分子伴侣功能失调会导致许多代谢、肿瘤、神经退行性疾病和心血管疾病。特别是，Hsp90伴侣机器涉及许多伴侣和辅助伴侣，通过复杂的相互作用网络，确保许多关键调控蛋白的折叠和功能。目前的信息表明，瞄准这台机器可能会对导致癌症和神经退行性疾病等人类疾病的功能失调的电路产生重大的组合影响。需要以选择性方式靶向Hsp90机器的新型小分子化合物。他们将提供工具和分子探针来进一步剖析这台机器的生物学，以更好地了解它在疾病病因和进展中的作用，并促进随后针对相关靶点的治疗学的发展。本应用旨在建立一种基于孕酮和糖皮质激素受体的高通量检测方法，这些受体是Hsp90的生理客户，也是Hsp90伴侣机器的核心组件(Hsp90、Hsp70、Hsp40、Hop和p23)。这项测试将大大促进对影响Hsp90机器功能核心的化学探针的发现。它还将为Hsp90α和β亚型的特定抑制剂提供长期追捧的筛选工具，并促进 活性化合物分子靶标的鉴定。 与公共健康相关：该项目旨在开发一种新的高通量分析方法，以发现新的分子伴侣抑制剂，这种抑制剂最终可能被开发为抗癌和其他人类疾病的药物。