New paradigms for Hsp90 inhibition

Hsp90 抑制的新范例

基本信息

批准号：
10000886
负责人：
Brian S J Blagg
金额：
$ 35.41万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2021-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10000886
关键词：
Amino Acids Antineoplastic Agents Binding Binding Sites Cardiotoxicity Cell Proliferation Client Clinical Trials Complex Crystallization Data Development Disease Dose Drug Design Evaluation Exhibits Frequencies Generations HSP 90 inhibition Heat shock proteins Heat-Shock Response Hepatotoxicity In Vitro Individual Lead MAPK7 gene Malignant Neoplasms Maximum Tolerated Dose Methods Molecular Chaperones Molecular Conformation N-terminal Patients Peripheral Nervous System Diseases Pharmaceutical Chemistry Pharmaceutical Preparations Process Property Protein Isoforms Proteins Reporting Schedule Side Signal Transduction Structure Toxic effect Validation antitumor agent base cancer therapy cell growth clinical candidate computer studies drug development in vivo inhibitor/antagonist myelination neuropeptide Y novel strategies protein degradation protein folding research clinical testing side effect small molecule inhibitor

项目摘要

The 90 kDa heat shock proteins (Hsp90) are responsible for the maturation of approximately 200 client protein substrates, most of which are associated with signaling cascades that regulate cellular growth and proliferation. Therefore, Hsp90 inhibition provides a novel approach toward the treatment of cancer as numerous signaling cascades can be derailed through inhibition of the Hsp90-dependent protein folding process. In this application, we propose to develop selective inhibitors of the Hsp90 Isoforms, Grp94, Hsp90α, and Hsp90β, using a structure-guided approach. In addition, we will perform side by side evaluation of these compounds against pan-inhibitors both in vitro and in vivo to validate our approach. Together, these methods will provide a new approach for selective inhibition of Hsp90 and will provide a new paradigm for anti-cancer drug development.

90 kDa 热休克蛋白 (Hsp90) 负责大约 200 种客户蛋白的成熟底物，其中大部分与调节细胞生长和的信号级联有关因此，Hsp90 抑制为治疗癌症提供了一种新方法。许多信号级联可以通过抑制 Hsp90 依赖性蛋白折叠而脱轨在此应用中，我们建议开发 Hsp90 同工型、Grp94、Hsp90α、的选择性抑制剂。和 Hsp90β，使用结构引导的方法此外，我们将对这些进行并行评估。在体外和体内针对泛抑制剂的化合物来验证我们的方法。将为选择性抑制Hsp90提供新途径，为抗癌提供新范式药物开发。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Structure Based Design of a Grp94-Selective Inhibitor: Exploiting a Key Residue in Grp94 To Optimize Paralog-Selective Binding.

DOI：
10.1021/acs.jmedchem.7b01608
发表时间：
2018-04-12
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Que NLS;Crowley VM;Duerfeldt AS;Zhao J;Kent CN;Blagg BSJ;Gewirth DT
通讯作者：
Gewirth DT

Selective Inhibition of the Hsp90α Isoform.

DOI：
10.1002/anie.202015422
发表时间：
2021-05-03
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
0
作者：
Mishra SJ;Khandelwal A;Banerjee M;Balch M;Peng S;Davis RE;Merfeld T;Munthali V;Deng J;Matts RL;Blagg BSJ
通讯作者：
Blagg BSJ

HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts.

DOI：
10.1016/j.jlr.2021.100114
发表时间：
2021
期刊：
Journal of lipid research
影响因子：
6.5
作者：
Pipalia NH;Saad SZ;Subramanian K;Cross A;Al-Motawa A;Garg K;Blagg BSJ;Neckers L;Helquist P;Wiest O;Ory DS;Maxfield FR
通讯作者：
Maxfield FR

The discovery and development of binimetinib for the treatment of melanoma.