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Hsp90B in Bladder Cancer

膀胱癌中的 Hsp90B

基本信息

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
起止时间：
2018-05-08 至 2022-04-30
项目状态：
已结题

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

项目摘要

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.

非常需要开发治疗癌症的新方法。热休克蛋白90蛋白折叠机制已经成为开发抗癌剂的重要目标。然而，Hsp 90负责约300种蛋白质折叠底物的折叠，这可能导致不期望的靶向毒性，并且可能是许多在临床试验中失败的Hsp 90靶向药物的原因。通过基于结构的方法，Hsp 90的异构体选择性抑制剂已被鉴定，并显示出对特定癌症的良好选择性和亲和力。因此，本申请的目标是优化这种新的抑制性支架以获得更大的亲和力/功效，评估特定Hsp 90亚型在癌症中的作用，并验证该亚型作为膀胱癌治疗靶点。