膀胱癌中的 Hsp90B-猫眼课题宝

膀胱癌中的 Hsp90B

批准号：

9922232

负责人：

Brian S J Blagg

金额：

$35.17万

依托单位：

UNIVERSITY OF NOTRE DAME

依托单位国家：

美国

项目类别：

财政年份：

2018

资助国家：

美国

项目状态：

已结题

起止时间：

2018-05-08 至 2022-04-30

来源：

https://reporter.nih.gov/project-details/9922232

关键词：

Affinity Animal Model Antineoplastic Agents Binding Binding Sites Cardiotoxicity Cells Client Clinical Clinical Trials Collaborations Complex Crystallization Data Development Disease Dose Drug Design Drug Targeting Exhibits Frequencies Generations Goals HSP 90 inhibition Heat shock proteins Heat-Shock Proteins 90 Heat-Shock Response Hepatotoxicity In Vitro Individual Lead MAPK7 gene Malignant Neoplasms Malignant neoplasm of urinary bladder Maximum Tolerated Dose Methods Molecular Chaperones Molecular Conformation N-terminal Pathogenesis Pathway interactions Patients Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacology Play Protein Isoforms Proteins Proteomics Reporting Research Personnel Role Schedule Signal Transduction Structure Study models Time Toxic effect Translating Validation antitumor agent base clinical candidate drug development in vivo inhibitor/antagonist interest knock-down molecular modeling myelination nanomolar neuropeptide Y novel anticancer drug protein degradation protein folding research clinical testing scaffold side effect

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中文摘要

翻译

开发治疗癌症的新方法是非常必要的。Hsp90蛋白质折叠机器具有一直是抗癌药物开发的重要靶点。然而，Hsp90负责折叠~300个蛋白质折叠底物，这可能会导致不希望看到的靶向毒性，并可能是许多Hsp90靶向药物在临床试验中失败的原因。通过基于结构的方法，Hsp90的异构体选择性抑制剂已经被发现，并被证明对特定的癌症具有良好的选择性和亲和力。因此，这项应用的目标是优化这种新的抑制性支架以获得更高的亲和力/有效性，评估特定的Hsp90亚型在癌症中的作用，并验证该亚型作为治疗膀胱癌的靶点。

英文摘要

The development of new methods to treat cancer is greatly needed. The Hsp90 protein folding machinery has been the target of significant interest for the development of anti-cancer agents. However, Hsp90 is responsible for the folding of ~300 protein folding substrates, which may lead to undesired on-target toxicity and may be responsible for many of the Hsp90-targeted drugs that have failed in clinical trials. Through a structure-based approach, an isoform-selective inhibitor of Hsp90 has been identified and shown to exhibit good selectivity and affinity against particular cancers. Consequently, the goal of this application is to optimize this new inhibitory scaffold for great affinity/efficacy, to evaluate the role of a specific Hsp90 isoform in cancer, and to validate this isoform as a target for the treatment of bladder cancer.

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