Traditional approaches in the development of small-molecule drugs typically aim to inhibit the biochemical activity of functional protein domains. In contrast, targeted protein degradation aims to reduce overall levels of disease-relevant proteins. Mechanistically, this can be achieved via chemical ligands that induce molecular proximity between an E3 ubiquitin ligase and a protein of interest, leading to ubiquitination and degradation of the protein of interest. This paradigm-shifting pharmacology promises to address several limitations inherent to conventional inhibitor design. Most notably, targeted protein degradation has the potential not only to expand the druggable proteome beyond the reach of traditional competitive inhibitors but also to develop therapeutic strategies of unmatched selectivity. This review briefly summarizes key challenges that remain to be addressed to deliver on these promises and to realize the full therapeutic potential of pharmacologic modulation of protein degradation pathways.

中文翻译：

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靶向蛋白质降解：当前和未来的挑战。

开发小分子药物的传统方法通常旨在抑制功能蛋白结构域的生化活性。相比之下，靶向蛋白质降解旨在降低疾病相关蛋白质的总体水平。从机制上讲，这可以通过化学配体来实现，化学配体诱导 E3 泛素连接酶和目标蛋白质之间的分子接近，从而导致目标蛋白质的泛素化和降解。这种范式转变的药理学有望解决传统抑制剂设计固有的一些局限性。最值得注意的是，靶向蛋白质降解不仅有可能将可药物蛋白质组扩展到传统竞争性抑制剂的范围之外，而且有可能开发出无与伦比的选择性治疗策略。本综述简要总结了为兑现这些承诺并实现蛋白质降解途径药理调节的全部治疗潜力而仍有待解决的关键挑战。