Development and Evaluation of Purine and Coumarin Based Hsp90 Inhibitors

 描述(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，其中许多与细胞信号直接相关，因此在恶性转化过程中经常被劫持。因此，通过抑制Hsp90，可以同时干扰多个信号通路。因此，Hsp90已成为一个很有前途的抗癌靶点，目前有17种抑制剂正在进行临床评估。不幸的是，所有这些分子都结合到Hsp90的N端结合部位，并在抑制Hsp90蛋白折叠机械的相同浓度下诱导有利于生存的热休克反应。最终的结果通常是细胞抑制活性和化疗耐药的可能性。与N-末端抑制剂不同，C-末端抑制剂可以分离这些活性，这为有用的抗癌药物的开发带来了意想不到的机会。事实上，C-末端抑制剂不会诱导热休克反应，从而诱导对许多癌细胞的凋亡，具有很高的分化选择性。第一个确定的C-末端抑制物是 Novobiocin，其IC50为~700微摩尔。在过去的几年里，我们对这种香豆素抗生素进行了修饰，并将其转化为一种潜在的临床先导化合物，具有~100 nm的活性。在这项建议中，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它们进行评估，以努力提供更多的证据来支持它们在临床上应用于各种癌症。

 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.