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Targeting the HSP90–CDC37–kinase chaperone cycle: A promising therapeutic strategy for cancer
Medicinal Research Reviews ( IF 13.3 ) Pub Date : 2021-04-12 , DOI: 10.1002/med.21807
Lei Wang 1, 2 , Qiuyue Zhang 1, 2 , Qidong You 1, 2
Affiliation  

Heat shock protein 90 (HSP90) is an indispensable molecular chaperone that facilitates the maturation of numerous oncoproteins in cancer cells, including protein kinases, ribonucleoproteins, steroid hormone receptors, and transcription factors. Although over 30 HSP90 inhibitors have steadily entered clinical trials, further clinical advancement has been restricted by their limited efficacy, inevitable heat shock response, and multiple side-effects, likely induced via an ATP inhibition mechanism. Since both ATP and various co-chaperones play essential roles in the HSP90 chaperone cycle to achieve integrated function, optimal therapeutics require an understanding of the dynamic interactions among HSP90, ATP, and cochaperones. To date, continuous research has promoted the exploration of the cochaperone cell division cycle 37 (CDC37) as a kinase-specific recognizer and has shown that the HSP90–CDC37–kinase complex is particularly relevant in cancers. Indeed, disrupting the HSP90–CDC37–kinase complex, rather than totally blocking the ATP function of HSP90, is emerging as an alternative way to avoid the limitations of current inhibitors. In this review, we first briefly introduce the HSP90–CDC37–kinase cycle and present the currently available approaches for inhibitor development targeting this cycle and provide insights into selective regulation of the kinase clients of HSP90 by more directional ways.

中文翻译:

靶向 HSP90-CDC37-激酶伴侣循环:一种有前途的癌症治疗策略

热休克蛋白 90 (HSP90) 是一种不可或缺的分子伴侣,可促进癌细胞中多种癌蛋白的成熟,包括蛋白激酶、核糖核蛋白、类固醇激素受体和转录因子。尽管超过 30 种 HSP90 抑制剂已稳步进入临床试验,但进一步的临床进展受到其有限的疗效、不可避免的热休克反应和多种副作用的限制,这些副作用可能是通过 ATP 抑制机制诱导的。由于 ATP 和各种辅助伴侣在 HSP90 伴侣循环中发挥重要作用以实现综合功能,因此最佳治疗需要了解 HSP90、ATP 和辅助伴侣之间的动态相互作用。迄今为止,持续的研究促进了将 cochaperone 细胞分裂周期 37 (CDC37) 作为激酶特异性识别器的探索,并表明 HSP90-CDC37-激酶复合物与癌症特别相关。事实上,破坏 HSP90-CDC37-激酶复合物,而不是完全阻断 HSP90 的 ATP 功能,正在成为一种避免当前抑制剂限制的替代方法。在这篇综述中,我们首先简要介绍了 HSP90-CDC37-激酶循环,并介绍了目前针对该循环开发抑制剂的可用方法,并提供了通过更定向的方式选择性调节 HSP90 激酶客户的见解。而不是完全阻断 HSP90 的 ATP 功能,正在成为一种避免当前抑制剂限制的替代方法。在这篇综述中,我们首先简要介绍了 HSP90-CDC37-激酶循环,并介绍了目前针对该循环开发抑制剂的可用方法,并提供了通过更定向的方式选择性调节 HSP90 激酶客户的见解。而不是完全阻断 HSP90 的 ATP 功能,正在成为一种避免当前抑制剂限制的替代方法。在这篇综述中,我们首先简要介绍了 HSP90-CDC37-激酶循环,并介绍了目前针对该循环开发抑制剂的可用方法,并提供了通过更定向的方式选择性调节 HSP90 激酶客户的见解。
更新日期:2021-04-12
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