Targeted protein degradation: expanding the toolbox.,Nature Reviews Drug Discovery

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Targeted protein degradation: expanding the toolbox.
Nature Reviews Drug Discovery ( IF 122.7 ) Pub Date : 2019-10-30 , DOI: 10.1038/s41573-019-0047-y
Matthieu Schapira _{1,

2} , Matthew F Calabrese ₃ , Alex N Bullock ₄ , Craig M Crews _{5,

6,

7}

Affiliation

Proteolysis-targeting chimeras (PROTACs) and related molecules that induce targeted protein degradation by the ubiquitin-proteasome system represent a new therapeutic modality and are the focus of great interest, owing to potential advantages over traditional occupancy-based inhibitors with respect to dosing, side effects, drug resistance and modulating 'undruggable' targets. However, the technology is still maturing, and the design elements for successful PROTAC-based drugs are currently being elucidated. Importantly, fewer than 10 of the more than 600 E3 ubiquitin ligases have so far been exploited for targeted protein degradation, and expansion of knowledge in this area is a key opportunity. Here, we briefly discuss lessons learned about targeted protein degradation in chemical biology and drug discovery and systematically review the expression profile, domain architecture and chemical tractability of human E3 ligases that could expand the toolbox for PROTAC discovery.

中文翻译：

靶向蛋白质降解：扩展工具箱。

靶向蛋白水解的嵌合体（PROTAC）和相关分子通过遍在蛋白-蛋白酶体系统诱导靶向蛋白降解代表了一种新的治疗方式，并且是人们关注的焦点，这是因为在剂量，侧面方面，它们相对于传统的基于占用的抑制剂具有潜在的优势。效果，耐药性和调节“非药物”目标。但是，该技术仍在日趋成熟，目前正在阐明成功使用基于PROTAC的药物的设计要素。重要的是，到目前为止，在600多种E3泛素连接酶中，只有不到10种被用于靶向蛋白质降解，而扩大这一领域的知识是一个关键的机会。这里，

更新日期：2019-11-01

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