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）：证明90 kDa热休克蛋白是非凡的癌症化学治疗靶标，这证明了20多个临床试验目前正在进行中。不幸的是，所有这些试验均基于N末端抑制剂，主要是Geldanamycin衍生的，它们表现出严重的配方，调度和给药困难，因为这些化合物诱导HSP的浓度相同，它们会诱导客户蛋白降解。 Neckers及其同事的先前研究确定HSP90包含一个C末端ATP结合位点，该结合位点与Coumarin抗生素相比与ATP相比。像N末端抑制剂一样，C末端结合结构域的抑制剂也会导致肿瘤细胞生长和增殖所需的Hsp90依赖性客户蛋白的降解。香豆素抗生素的主要缺点是它们与HSP90（IC50约700个微摩尔）弱结合；但是，我们小组的最新研究导致化合物比这些天然产物高1000倍。通过SAR研究，我们能够确定对HSP90抑制作用重要的功能，并学会了如何以先前未实现的方式调节HSP90。因此，我们开发了诱导HSP低浓度的化合物，这些化合物将变性蛋白重塑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，通过该机制绕过诊所中N末端抑制剂观察到的困难。在此应用中，我们建议基于在我的实验室中开发的嘌呤和COMFA模型进一步开发抗肿瘤剂，该模型将有助于构建HSP90 C90 C末端结合位点的更有效，更可溶的抑制剂。除了我们的特殊初步体内研究外，还建议进一步研究其他癌症体内模型中最活跃的化合物。由于这些研究的结果，我们认为我们可以提供一个新的平台，可以通过调节HSP90蛋白质折叠机械来基于或实现新药来治疗癌症。公共卫生相关性：该提案的目的是通过瞄准负责折叠蛋白的蛋白质（HSP90）来攻击多种具有癌症的酶，因为必须折叠所有蛋白质才能活跃。尽管针对HSP90的化合物正在进行临床试验，但事实证明它们表现出有害特性。我们已经确定了没有表现出这些有害特性的分子，并且在癌症的初步动物模型中被证明是出色的。我们计划继续并开发这些药物。