Old and New Approaches to Target the Hsp90 Chaperone.
Old and New Approaches to Target the Hsp90 Chaperone.
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DOI：
10.2174/1568009619666191202101330
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发表时间：
2020
影响因子：
3
通讯作者：
Blagg BSJ
中科院分区：
文献类型：
--
作者：
Sanchez J;Carter TR;Cohen MS;Blagg BSJ
热休克蛋白（Hsp 90）是一种分子伴侣，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质稳定。Hsp 90不仅对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下也至关重要，如癌症和神经退行性疾病。由于其能够影响许多客户蛋白的磷酸化，自20世纪90年代早期以来，抑制Hsp 90一直是一种有吸引力的抗癌方法，当时研究人员在Hsp 90的氨基末端上鉴定了用于多种癌症的可药物化靶标。从那时起，17种靶向分子伴侣N端结构域的Hsp 90抑制剂已进入临床试验。然而，到目前为止，FDA还没有批准将其作为癌症单一疗法。在这些试验中，在N-末端结构域抑制Hsp 90观察到的主要限制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，临床前和临床研究继续表明，Hsp 90抑制剂有效地靶向癌细胞死亡并减少肿瘤进展，支持开发新型Hsp 90抑制剂的基本原理。在这里，我们对临床试验中使用的Hsp 90抑制剂进行了深入的概述。最后，我们提出了目前的转变，在该领域的目标，以及异构体选择性抑制剂的发展，以绕过目前的热休克蛋白90抑制剂的陷阱，提高临床试验的结果。
The 90-kDa heat shock protein (Hsp90) is a molecular chaperone that ensures cellular proteostasis by maintaining the folding, stabilization, activation, and degradation of over 400 client proteins. Hsp90 is not only critical for routine protein maintenance in healthy cells, but also during states of cellular stress, such as cancer and neurodegenerative diseases. Due to its ability to affect phosphorylation of numerous client proteins, inhibition of Hsp90 has been an attractive anticancer approach since the early 1990’s, when researchers identified a druggable target on the amino terminus of Hsp90 for a variety of cancers. Since then, 17 Hsp90 inhibitors that target the chaperone’s N-terminal domain, have entered clinical trials. None, however, have been approved thus far by the FDA as a cancer monotherapy. In these trials, a major limitation observed with Hsp90 inhibition at the N-terminal domain was dose-limiting toxicities and relatively poor pharmacokinetic profiles. Despite this, preclinical and clinical research continues to show that Hsp90 inhibitors effectively target cancer cell death and decrease tumor progression supporting the rationale for the development of novel Hsp90 inhibitors. Here, we present an in-depth overview of the Hsp90 inhibitors used in clinical trials. Finally, we present current shifts in the field related to targeting the carboxy-terminal domain of Hsp90 as well as to the development of isoform-selective inhibitors as a means to bypass the pitfalls of current Hsp90 inhibitors and improve clinical trial outcomes.