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：
8184035
负责人：
Brian S J Blagg
金额：
$ 36.93万
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 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8184035
关键词：
17-(Allylamino)-17-demethoxygeldanamycin Ablation Academia Affinity Animal Cancer Model Antibiotics Antineoplastic Agents Binding Binding Sites Biological Availability Biological Factors Bypass C-terminal Cell Proliferation Cells Client Clinic Clinical Clinical Treatment Clinical Trials Collaborations Coumarins Development Diphosphates Dose Drug Formulations Drug Industry Drug Kinetics Drug resistance Drug toxicity Enzymes Evaluation Exhibits Frequencies Geldanamycin Goals Growth Head and Neck Squamous Cell Carcinoma Heat shock proteins Heat-Shock Response Hepatotoxicity Human In Vitro Inhibitory Concentration 50 Intervention Laboratories Lead Learning Ligands Location Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Maximum Tolerated Dose Methods Modeling Modification Molecular Chaperones Molecular Conformation N-terminal Neurodegenerative Disorders Non-Malignant Novobiocin Nucleotides Oncogenic Patients Pharmaceutical Preparations Plague Pre-Clinical Model Preparation Process Property Protein Family Proteins Purines Schedule Solubility Structure System Toxic effect Work alpha benzopyrone analog antitumor drug base cancer cell cancer therapy cell growth clinical application design improved in vivo in vivo Model inhibitor/antagonist model development neoplastic cell novel piperidine polypeptide prevent protein degradation protein folding purine research clinical testing scaffold tumor tumor growth tumor progression

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 extensive studies and elucidation of the C- terminal binding site, we 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 develop anticancer agents based on our recently elucidated C-terminal binding site in an effort to produce agents suitable for clinical evaluation. In addition, we plan to investigate the most active compounds in additional in vivo models of cancer PUBLIC HEALTH RELEVANCE: Current Hsp90 inhibitors in clinical trials 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. Therefore, the goal of this proposal is to attack multiple cancer-enabling enzymes by inhibiting Hsp90 at a new location and to produce new clinical candidates for the treatment of cancer

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> 1000倍，比这些天然产品更活跃。通过广泛的研究和阐明c末端结合位点，我们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，我们建议基于我们最近阐明的C末端结合位点开发抗癌药，以产生适合临床评估的药物。此外，我们计划研究其他体内癌症模型中最活跃的化合物公共卫生相关性：临床试验中当前的HSP90抑制剂表现出有害特性，证明难以克服。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。因此，该提案的目的是通过在新位置抑制HSP90并生产新的临床候选者来攻击多种增强癌症的酶。