Department of Chemistry and Biochemistry, The Warren Family Research Center for Drug Discovery and Development, The University of Notre Dame, Notre Dame, IN, USA.
Adv Exp Med Biol. 2020;1243:135-146. doi: 10.1007/978-3-030-40204-4_9.
Molecular chaperones are responsible for maintaining intracellular protein quality control by facilitating the conformational maturation of new proteins as well as the refolding of denatured proteins. While there are several classes of molecular chaperones in the cell, this chapter will focus solely on the small molecule modulation of Hsp90, the 90 kDa heat shock protein. Hsp90 is not only responsible for folding nascent proteins, but it also regulates the triage of numerous client proteins through partnering with the ubiquitin-proteasome pathway. Consequently, Hsp90 plays critical role in maintaining the protein homeostasis (proteostasis) network within the cell and is required for the activation/maturation of more than 300 client protein substrates. Many of the clients that depend upon Hsp90 are overexpressed or mutated during malignant transformation. This often renders the clients thermodynamically unstable and dependent on Hsp90 for stability. This phenomenon results in an oncogenic 'addiction' to the Hsp90 protein folding machinery as Hsp90 maintains onco-client proteins. Furthermore, Hsp90-dependent substrates are associated with all ten hallmarks of cancer, making Hsp90 an attractive target for the development of cancer chemotherapeutics. In fact, 17 small molecule inhibitors of Hsp90 have been developed and clinically evaluated for the treatment of cancer. Unfortunately, most of these molecules have failed for various reasons, necessitating a new approach to modulate the Hsp90 protein folding machine.
分子伴侣负责通过促进新蛋白质的构象成熟以及变性蛋白质的重折叠来维持细胞内蛋白质质量控制。虽然细胞中有几类分子伴侣，但本章将仅关注小分子对 Hsp90 的调节，Hsp90 是一种 90kDa 的热休克蛋白。Hsp90 不仅负责折叠新生蛋白质，还通过与泛素蛋白酶体途径合作来调节众多客户蛋白质的分类。因此，Hsp90 在维持细胞内蛋白质动态平衡（蛋白质稳态）网络中起着关键作用，并且是激活/成熟 300 多个客户蛋白质底物所必需的。许多依赖 Hsp90 的客户蛋白在恶性转化过程中过度表达或发生突变。这通常会使客户蛋白热力学不稳定并依赖 Hsp90 来稳定。这种现象导致了对 Hsp90 蛋白质折叠机制的致癌“成瘾”，因为 Hsp90 维持着致癌客户蛋白。此外，Hsp90 依赖性底物与癌症的所有十个标志都有关联，这使得 Hsp90 成为开发癌症化学疗法的有吸引力的靶点。事实上，已经开发并临床评估了 17 种 Hsp90 的小分子抑制剂来治疗癌症。不幸的是，由于各种原因，这些分子中的大多数都失败了，因此需要一种新的方法来调节 Hsp90 蛋白质折叠机器。
