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Targeting the core components of the Hsp90 chaperoning machine

瞄准Hsp90陪伴机核心部件

基本信息

批准号：
8651503
负责人：
Ahmed Chadli
金额：
$ 25.58万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8651503
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 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 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 screening small molecule therapeutic development tool transcription factor

项目摘要

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.

描述（由申请人提供）：分子伴侣是维持健康蛋白质组和细胞稳态的关键参与者。分子伴侣的功能失调导致许多代谢、肿瘤、神经退行性和心血管疾病。特别是Hsp90分子伴侣机制，涉及许多分子伴侣和辅助分子伴侣，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，靶向这台机器可能对导致癌症和神经退行性疾病等人类疾病的功能障碍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，以进一步剖析这种机器的生物学，以更好地了解其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方法的开发。本申请旨在开发一种基于孕酮和糖皮质激素受体的高通量测定法，孕酮和糖皮质激素受体是Hsp90的生理客户，以及Hsp90伴侣机器的核心组分（Hsp90、Hsp70、Hsp40、Hop和p23）。这种测定将显著增强影响Hsp90机器功能核心的化学探针的发现。它还将为Hsp90 α和β亚型的特异性抑制剂提供长期寻求的筛选工具，并促进活性化合物分子靶点的鉴定。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Progesterone receptor chaperone complex-based high-throughput screening assay: identification of capsaicin as an inhibitor of the Hsp90 machine.

DOI：
10.1177/1087057114549147
发表时间：
2015-02
期刊：
Journal of biomolecular screening
影响因子：
0
作者：
Patwardhan CA;Alfa E;Lu S;Chadli A
通讯作者：
Chadli A

Bioactive metabolites from Chaetomium aureum: structure elucidation and inhibition of the Hsp90 machine chaperoning activity.

DOI：
10.1016/j.bmc.2014.11.021
发表时间：
2015-01-01
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Kabbaj FZ;Lu S;Faouzi Mel A;Meddah B;Proksch P;Cherrah Y;Altenbach HJ;Aly AH;Chadli A;Debbab A
通讯作者：
Debbab A