Inhibitors of the AAA+ chaperone p97.
Inhibitors of the AAA+ chaperone p97.
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DOI：
10.3390/molecules20023027
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发表时间：
2015-02-12
期刊：
影响因子：
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通讯作者：
La Clair JJ
中科院分区：
文献类型：
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作者：
Chapman E;Maksim N;de la Cruz F;La Clair JJ
值得注意的是，像蛋白质质量控制这样普遍存在的途径可以靶向治疗癌症。硼替佐米是一种蛋白酶体抑制剂，10多年前首次被美国食品和药物管理局（FDA）批准用于治疗难治性骨髓瘤，后来扩展到淋巴瘤。它的使用使骨髓瘤患者的生存率提高了三年之多。这一成功之后，最近加速批准了天然产物衍生的蛋白酶体抑制剂卡非佐米（Kyprolis®），用于治疗硼替佐米耐药的多发性骨髓瘤患者。这两种药物的成功验证了蛋白质质量控制作为对抗特定癌症的可行靶点，但回避了为什么蛋白酶体抑制剂仅限于淋巴瘤和骨髓瘤的问题？最近，这些限制鼓励在蛋白质质量控制系统中寻找额外的靶点，这些靶点可能提供更高的癌细胞特异性，增强的临床实用性，更低的耐药率，降低的毒性和减轻的副作用。一个有希望的靶标是p97，一种与各种细胞活性（AAA+）伴侣相关的ATP酶。p97在蛋白质质量控制以及与癌症相关的多种其它细胞功能中占有重要地位。十多年前，人们确定在许多形式的癌症中p97的上调与不良的临床结果相关。由于这些最初的发现，对这一观察的机械解释已经部分阐明，但缺乏细节。可以理解的是，考虑到这种临床相关性，细胞内的无数作用及其在蛋白质质量控制中的重要性，p97已成为潜在的治疗靶点。本文综述了p97的小分子抑制剂的发现的努力，提供了一个概要的努力，平行的优秀评论，目前存在的p97的结构，功能和生理学。
It is remarkable that a pathway as ubiquitous as protein quality control can be targeted to treat cancer. Bortezomib, an inhibitor of the proteasome, was first approved by the US Food and Drug Administration (FDA) more than 10 years ago to treat refractory myeloma and later extended to lymphoma. Its use has increased the survival rate of myeloma patients by as much as three years. This success was followed with the recent accelerated approval of the natural product derived proteasome inhibitor carfilzomib (Kyprolis®), which is used to treat patients with bortezomib-resistant multiple myeloma. The success of these two drugs has validated protein quality control as a viable target to fight select cancers, but begs the question why are proteasome inhibitors limited to lymphoma and myeloma? More recently, these limitations have encouraged the search for additional targets within the protein quality control system that might offer heightened cancer cell specificity, enhanced clinical utility, a lower rate of resistance, reduced toxicity, and mitigated side effects. One promising target is p97, an ATPase associated with various cellular activities (AAA+) chaperone. p97 figures prominently in protein quality control as well as serving a variety of other cellular functions associated with cancer. More than a decade ago, it was determined that up-regulation of p97 in many forms of cancer correlates with a poor clinical outcome. Since these initial discoveries, a mechanistic explanation for this observation has been partially illuminated, but details are lacking. Understandably, given this clinical correlation, myriad roles within the cell, and its importance in protein quality control, p97 has emerged as a potential therapeutic target. This review provides an overview of efforts towards the discovery of small molecule inhibitors of p97, offering a synopsis of efforts that parallel the excellent reviews that currently exist on p97 structure, function, and physiology.