Old and New Approaches to Target the Hsp90 Chaperone

doi:10.2174/1568009619666191202101330
摘要

90 kDa热休克蛋白（Hsp90）是一种分子伴侣，可通过维持400多种客户蛋白的折叠，稳定，活化和降解来确保细胞蛋白水解。 Hsp90不仅对于健康细胞中的常规蛋白质维持至关重要，而且在细胞应激状态（例如癌症和神经退行性疾病）中也很重要。由于具有影响多种客户蛋白质磷酸化的能力，自1990年代初以来，抑制Hsp90一直是一种有吸引力的抗癌方法，当时研究人员在Hsp90的氨基末端确定了可治疗多种癌症的靶标。从那以后，针对分子伴侣N末端结构域的17种Hsp90抑制剂进入了临床试验。但是，到目前为止，没有一种药物被FDA批准为癌症的单一疗法。在这些试验中，在N末端域抑制Hsp90的主要局限性是剂量限制性毒性和相对较差的药代动力学特征。尽管如此，临床前和临床研究仍显示Hsp90抑制剂有效地靶向癌细胞死亡并降低了肿瘤进展，为开发新型Hsp90抑制剂提供了理论依据。在这里，我们提供了在临床试验中使用的Hsp90抑制剂的深入概述。最后，我们提出了与靶向Hsp90的羧基末端结构域以及同工型选择性抑制剂的开发相关的领域的当前变化，以绕过当前Hsp90抑制剂的陷阱并改善临床试验结果。
关键词: 癌症，伴侣蛋白，格尔德霉素，Grp94，Hsp90，新霉素，TAS-116，TRAP1。
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图形摘要

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DOI https://dx.doi.org/10.2174/1568009619666191202101330	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576
当代肿瘤药物靶点

针对Hsp90伴侣的新旧方法

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当代肿瘤药物靶点

针对Hsp90伴侣的新旧方法

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