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: 9600723
• 负责人: Brian S J Blagg
• 金额: $ 44.39万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9600723
• 关键词: Development; Evaluation; Purine; Coumarin; Based

 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）：Hsp90 是一种分子伴侣，负责 200 多种客户蛋白底物的构象成熟，其中许多底物与细胞信号传导直接相关，因此在恶性转化过程中经常被劫持。 Hsp90抑制，可同时破坏多种信号通路，因此Hsp90已成为一个有前景的抗癌靶点，目前有17种抑制剂正在进行临床。不幸的是，所有这些分子都与 Hsp90 N 端结合位点结合，并且在抑制 Hsp90 蛋白折叠机制的相同浓度下也会诱导促存活热休克反应。最终结果通常是细胞抑制活性和抑制作用。与 N 端抑制剂不同，C 端抑制剂可以隔离这些活性，这为开发有用的抗癌药物带来了不可预见的机会。抑制剂不会诱导热休克反应，因此能够以高差异选择性诱导多种癌细胞凋亡。第一个 C 末端抑制剂被鉴定出来。 新生霉素，其 IC50 值为约 700 微摩尔 在过去的几年中，我们对这种香豆素抗生素进行了修饰，并将其转化为具有约 100 nM 活性的潜在临床先导化合物。类化合物，并在头颈鳞状细胞癌的动物模型中对其进行评估，以提供额外的证据来支持其针对多种癌症的临床应用。