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

• 批准号: 9107340
• 负责人: Brian S J Blagg
• 金额: $ 35.99万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-19 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9107340
• 关键词: Ablation; Academia; Affinity; Animal Cancer Model; Animal Model; Antibiotics; Antineoplastic Agents; Apoptosis; Attention; Binding; Binding Sites; Biological Availability; C-terminal; Cells; Cetuximab; Cisplatin; Client; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Coumarins; Cytostatics; Development; Dose; Drug Industry; Drug Kinetics; Drug resistance; Enzymes; Evaluation; Exhibits; Frequencies; Geldanamycin; Geometry; Goals; Growth; HSP 90 inhibition; Head and Neck Squamous Cell Carcinoma; Health; Heat-Shock Proteins 70; Heat-Shock Response; Hepatotoxicity; In Vitro; 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; Plague; Preparation; Process; Property; Protein Family; Proteins; Purines; Resistance; Schedule; Signal Pathway; Signal Transduction; Solubility; Structure; System; Time; Toxic effect; Toxicity Tests; Up-Regulation; Validation; Work; analog; antitumor drug; base; cancer cell; clinical application; computer studies; design; diphenyl; improved; in vivo; inhibitor/antagonist; model development; nanomolar; novel; polypeptide; prevent; protein degradation; protein folding; research clinical testing; scaffold; tumor

 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（由申请人提供）：Hsp 90是一种分子伴侣，负责200多种客户蛋白底物的构象成熟，其中许多与细胞信号传导直接相关，因此在恶性转化期间经常被劫持。因此，通过抑制Hsp 90，可以同时破坏多个信号传导途径。因此，Hsp 90已成为一个有前途的抗癌靶点，目前有17种抑制剂正在进行临床评估。不幸的是，所有这些分子都与Hsp 90的N-末端结合位点结合，并且在它们抑制Hsp 90蛋白折叠机制的相同浓度下也诱导促存活热休克反应。最终结果通常是细胞生长抑制活性和潜在的化疗耐药性。与N-末端抑制剂不同，C-末端抑制剂可以分离这些活性，这为开发有用的抗癌剂带来了不可预见的机会。事实上，C-末端抑制剂不诱导热休克反应，因此，诱导针对许多癌细胞的凋亡具有高差异选择性。第一个发现的C-末端抑制剂是 新生霉素，其表现出约700微摩尔的IC 50值。在过去的几年中，我们已经修改了这种香豆素抗生素，并将其转化为一种潜在的临床先导化合物，其活性约为100 nM。在这项提案中，我们的目标是进一步开发这类化合物，并在头颈部鳞状细胞癌的动物模型中对其进行评估，以提供更多的证据来支持其对各种癌症的临床应用。