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：
7905053
负责人：
Brian S J Blagg
金额：
$ 35.57万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-19 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7905053
关键词：
17-(Allylamino)-17-demethoxygeldanamycin Ablation Academia Affinity Animal Cancer Model Animal Model Animals Antibiotics Area Binding Binding Sites Biological Biological Assay Biological Availability Biological Factors Bypass C-terminal Cells Client Clinic Clinical Treatment Clinical Trials Collaborations Coumarins Data Development Dose Drug Delivery Systems Drug Formulations Drug Industry Drug Kinetics Drug resistance Enzymes Evaluation Exhibits Funding Geldanamycin Goals Grant Growth Hand Head and Neck Squamous Cell Carcinoma Heat shock proteins Heat-Shock Response Hepatotoxicity Inhibitory Concentration 50 Intervention Laboratories Lead Learning Libraries Ligands Malignant - descriptor Malignant Neoplasms Malignant neoplasm of thyroid Methods Modeling Modification Molecular Chaperones Molecular Conformation Mus N-terminal Neurodegenerative Disorders Non-Malignant Novobiocin Nucleotides Oncogenic Pharmaceutical Preparations Plague Preparation Process Property Protein Family Proteins Purines Reporting Schedule Side Solubility Structure Structure-Activity Relationship Therapeutic Thyroid Gland Time Toxic effect Validation Work alpha benzopyrone analog antitumor agent antitumor drug base cancer cell cancer therapy cell growth clinical application comparative efficacy design improved in vivo in vivo Model inhibitor/antagonist innovation meetings neoplastic cell novel polypeptide prevent protein degradation protein folding public health relevance purine scaffold sugar tumor

项目摘要

DESCRIPTION (provided by applicant): The 90 kDa heat shock proteins are proving to be extraordinary cancer chemotherapeutic targets as evidenced by the fact that more than 20 clinical trials are currently in progress. Unfortunately, all of these trials are based upon N-terminal inhibitors, primarily geldanamycin- derived, which exhibit serious formulation, scheduling and dosing difficulties as these compounds induce Hsp's at the same concentration they induce client protein degradation. Previous studies by Neckers and coworkers determined that Hsp90 contains a C-terminal ATP binding site that bound coumarin antibiotics competitively versus ATP. Like N-terminal inhibitors, inhibitors of the C-terminal binding domain also cause the degradation of Hsp90-dependent client proteins required for tumor cell growth and proliferation. A major drawback of the coumarin antibiotics is that they bind weakly to Hsp90 (IC50 approximately 700 micromolar); however, recent studies by our group have led to compounds ~1000 fold more active than these natural products. Through SAR studies we have been able to identify functionalities important for Hsp90 inhibition and have learned how to modulate Hsp90 in ways not previously realized. Thus, we have developed compounds that induce Hsp's at low concentrations that refold denatured proteins as a new method to treat various neurodegenerative diseases. In contrast, we have constructed molecules that inhibit Hsp90 without inducing Hsp's, and therefore provide a mechanism by which to bypass difficulties observed with N-terminal inhibitors in the clinic. In this application we propose to further develop the anti-tumor agents based on a purine and CoMFA model developed in my laboratory that will aid in the construction of more efficacious and soluble inhibitors of the Hsp90 C-terminal binding site. In addition to our extraordinary preliminary in vivo studies, it is proposed to further investigate the most active compounds in additional in vivo models of cancer. As a consequence of these studies, we believe we can provide a new platform for which new drugs can be based or realized for the treatment of cancer via modulation of the Hsp90 protein folding machinery. PUBLIC HEALTH RELEVANCE: The goal of this proposal is to attack multiple cancer-enabling enzymes by targeting a protein (Hsp90) that is responsible for folding them, as all proteins must be folded to become active. Although clinical trials are in progress for compounds that target Hsp90, they exhibit detrimental properties that are proving difficult to overcome. We have identified molecules that do not exhibit these deleterious properties and have proven to be exceptional in preliminary animal models of cancer. We plan to continue and develop these drugs.

描述（由申请人提供）：90 kDa 热休克蛋白被证明是非凡的癌症化疗靶点，目前正在进行的 20 多项临床试验证明了这一点。不幸的是，所有这些试验都是基于N-末端抑制剂，主要是格尔德霉素衍生的，其表现出严重的配制、安排和剂量困难，因为这些化合物诱导Hsp's的浓度与诱导客户蛋白降解的浓度相同。 Neckers 及其同事之前的研究确定，Hsp90 含有一个 C 末端 ATP 结合位点，该位点与 ATP 竞争性地结合香豆素抗生素。与 N 端抑制剂一样，C 端结合域的抑制剂也会导致肿瘤细胞生长和增殖所需的 Hsp90 依赖性客户蛋白降解。香豆素类抗生素的一个主要缺点是它们与 Hsp90 的结合较弱（IC50 约为 700 微摩尔）；然而，我们小组最近的研究发现化合物的活性比这些天然产物高约 1000 倍。通过 SAR 研究，我们已经能够确定对 Hsp90 抑制很重要的功能，并了解如何以以前未实现的方式调节 Hsp90。因此，我们开发了能够在低浓度下诱导 Hsp 的化合物，从而重新折叠变性蛋白质，作为治疗各种神经退行性疾病的新方法。相比之下，我们构建了抑制 Hsp90 而不诱导 Hsp 的分子，因此提供了一种机制来绕过临床中使用 N 末端抑制剂观察到的困难。在此应用中，我们建议进一步开发基于我实验室开发的嘌呤和 CoMFA 模型的抗肿瘤药物，这将有助于构建更有效和可溶的 Hsp90 C 末端结合位点抑制剂。除了我们非凡的初步体内研究之外，还建议进一步研究其他体内癌症模型中最活跃的化合物。作为这些研究的结果，我们相信我们可以提供一个新平台，通过调节 Hsp90 蛋白折叠机制，可以基于该平台或实现新药物来治疗癌症。公共健康相关性：该提案的目标是通过针对负责折叠酶的蛋白质 (Hsp90) 来攻击多种致癌酶，因为所有蛋白质都必须折叠才能变得活跃。尽管针对 Hsp90 的化合物的临床试验正在进行中，但它们表现出难以克服的有害特性。我们已经鉴定出不表现出这些有害特性的分子，并已证明在初步的癌症动物模型中表现出色。我们计划继续开发这些药物。