Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors

基于嘌呤和香豆素的 Hsp90 抑制剂的开发和评价

基本信息

批准号：
9514012
负责人：
Brian S J Blagg
金额：
$ 35.33万
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：
2018-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514012
关键词：
Ablation Academia Affinity Animal Cancer Model Animal Model Antibiotics Antineoplastic Agents Apoptosis Attention Binding Binding Sites Biological Biological Availability C-terminal Cetuximab Cisplatin Client Clinical Clinical Trials Collaborations Coumarins Cytostatics Development Dimensions Dose Drug Industry Drug Kinetics Drug resistance Enzymes Evaluation Exhibits Frequencies Geldanamycin Geometry Goals Growth HSP 90 inhibition Head and Neck Squamous Cell Carcinoma Heat-Shock Proteins 70 Heat-Shock Response Hepatotoxicity In Vitro Individual Intervention Laboratories Lead Ligands Malignant - descriptor Malignant Neoplasms Maximum Tolerated Dose Modeling Modification Molecular Chaperones Molecular Conformation N-terminal Neck Neoplasms Non-Malignant Novobiocin Nucleotides Oncogenic Patients Pharmaceutical Preparations Preparation Process Property Protein Family Proteins Purines Resistance Schedule Signal Pathway Signal Transduction Solubility Structure System Time Toxic effect Toxicity Tests Up-Regulation Validation analog anti-cancer antitumor drug base cancer cell cancer therapy clinical application computer studies design diphenyl improved in vivo inhibitor/antagonist model development nanomolar novel polypeptide prevent protein degradation protein folding public health relevance research clinical testing scaffold tumor

项目摘要

DESCRIPTION (provided by applicant): Hsp90 is a molecular chaperone that is responsible for the conformational maturation of more than 200 client protein substrates, many of which are directly associated with cell signaling, and thus, are often hijacked during malignant transformation. Consequently, through Hsp90 inhibition, multiple signaling pathways can be disrupted simultaneously. As a result, Hsp90 has emerged as a promising anti-cancer target, and there are currently 17 inhibitors undergoing clinical evaluation. Unfortunately, all of these molecule bind to the Hsp90 N-terminal binding site, and also induce the pro-survival heat shock response at the same concentration they inhibit the Hsp90 protein folding machinery. The net result is generally, cytostatic activity and the potential for chemotherapeutic resistance. Unlike N-terminal inhibitors, C-terminal inhibitors can segregate these activities, which have led to unforeseen opportunities for the development of useful anti-cancer agents. In fact, C-terminal inhibitors do not induce the heat shock response and consequently, induce apoptosis against many cancer cells with high differential selectivity. The first C-terminal inhibitor identified was novobiocin, which manifests an IC50 value of ~700 micromolar. During the past few years, we have modified this coumarin antibiotic and transformed it into a potential clinical lead compound that exhibits ~100 nM activity. In this proposal, we aim to further develop this class of compounds and to evaluate them in animal models of head and neck squamous cell carcinoma in an effort to provide additional evidence to support their clinical application against a varietyof cancers.

描述（由适用提供）：HSP90是一种分子链酮，负责200多个客户蛋白蛋白底物的构象成熟，其中许多底物与细胞信号直接相关，因此通常在恶性转化期间被劫持。因此，通过HSP90抑制，可以简单地破坏多个信号通路。结果，HSP90已成为承诺的抗癌靶标，目前有17个正在接受临床评估的抑制剂。不幸的是，所有这些分子都与Hsp90 N末端结合位点结合，并在相同浓度下诱导促阳离子热休克响应，它们抑制HSP90蛋白折叠机械。净结果通常是细胞抑制活性和化学疗法抗性的潜力。与N末端抑制剂不同，C末端抑制剂可以隔离这些活动，这导致了不可预见的有用抗癌药物的机会。实际上，C末端抑制剂不会诱导热休克反应，因此会诱导许多具有高差异选择性的癌细胞的凋亡。确定的第一个C末端抑制剂是 Novobiocin，其表现为〜700微摩尔的IC50值。在过去的几年中，我们对这种香豆素抗生素进行了修饰，并将其转化为潜在的临床铅化合物，表现出约100 nm活性。在此提案中，我们旨在进一步开发此类化合物，并在头颈部鳞状细胞癌的动物模型中评估它们，以提供更多证据，以支持其针对各种癌症的临床应用。

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Novologue Therapy Requires Heat Shock Protein 70 and Thioredoxin-Interacting Protein to Improve Mitochondrial Bioenergetics and Decrease Mitophagy in Diabetic Sensory Neurons.

DOI：
10.1021/acschemneuro.1c00340
发表时间：
2021-08-18
期刊：
ACS chemical neuroscience
影响因子：
5
作者：
Rodriguez YA;Kaur S;Nolte E;Zheng Z;Blagg BSJ;Dobrowsky RT
通讯作者：
Dobrowsky RT

Heat shock response and insulin-associated neurodegeneration.

DOI：
10.1016/j.tips.2011.11.001
发表时间：
2012-03
期刊：
Trends in pharmacological sciences
影响因子：
13.8
作者：
Urban MJ;Dobrowsky RT;Blagg BS
通讯作者：
Blagg BS

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma.

DOI：
10.1080/17460441.2016.1201057
发表时间：
2016-09
期刊：
Expert opinion on drug discovery
影响因子：
6.3
作者：
Kim A;Cohen MS
通讯作者：
Cohen MS

Engineering an antibiotic to fight cancer: optimization of the novobiocin scaffold to produce anti-proliferative agents.

DOI：
10.1021/jm200148p
发表时间：
2011-06-09
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Zhao H;Donnelly AC;Kusuma BR;Brandt GE;Brown D;Rajewski RA;Vielhauer G;Holzbeierlein J;Cohen MS;Blagg BS
通讯作者：
Blagg BS

Modulating molecular chaperones improves sensory fiber recovery and mitochondrial function in diabetic peripheral neuropathy.

DOI：
10.1016/j.expneurol.2012.03.005
发表时间：
2012-05
期刊：
EXPERIMENTAL NEUROLOGY
影响因子：
5.3
作者：
Urban, Michael J.;Pan, Pan;Farmer, Kevin L.;Zhao, Huiping;Blagg, Brian S. J.;Dobrowsky, Rick T.
通讯作者：
Dobrowsky, Rick T.