CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
ACS Chem Biol. 2024 Oct 18;19(10):2089-2102. doi: 10.1021/acschembio.4c00191. Epub 2024 Sep 12.
Targeted protein degradation (TPD) is an emerging pharmacologic strategy. It relies on small-molecule "degraders" that induce proximity of a component of an E3 ubiquitin ligase complex and a target protein to induce target ubiquitination and subsequent proteasomal degradation. Essentially, degraders thus expand the function of E3 ligases, allowing them to degrade proteins they would not recognize in the absence of the small molecule. Over the past decade, insights gained from identifying, designing, and characterizing various degraders have significantly enhanced our understanding of TPD mechanisms, precipitating in rational degrader discovery strategies. In this Account, I aim to explore how these insights can be extrapolated to anticipate both opportunities and challenges of utilizing the overarching concept of proximity-inducing pharmacology to manipulate other cellular circuits for the dissection of biological mechanisms and for therapeutic purposes.
靶向蛋白降解（TPD）是一种新兴的药物研发策略。它依赖于小分子“降解剂”，诱导 E3 泛素连接酶复合物的一个成分和目标蛋白的接近，以诱导目标蛋白泛素化和随后的蛋白酶体降解。从本质上讲，降解剂因此扩展了 E3 连接酶的功能，使它们能够降解在没有小分子的情况下它们不会识别的蛋白质。在过去的十年中，通过鉴定、设计和表征各种降解剂获得的见解极大地增强了我们对 TPD 机制的理解，从而促成了合理的降解剂发现策略。在本述评中，我旨在探讨如何推断这些见解，以预测利用诱导接近药理学的总体概念来操纵其他细胞回路以剖析生物学机制和治疗目的的机会和挑战。
