Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of one ligand that binds to a protein of interest (POI) and another that can recruit an E3 ubiquitin ligase. The chemically-induced proximity between the POI and E3 ligase results in ubiquitination and subsequent degradation of the POI by the ubiquitin-proteasome system (UPS). The event-driven mechanism of action (MOA) of PROTACs offers several advantages compared to traditional occupancy-driven small molecule inhibitors, such as a catalytic nature, reduced dosing and dosing frequency, a more potent and longer-lasting effect, an added layer of selectivity to reduce potential toxicity, efficacy in the face of drug-resistance mechanisms, targeting nonenzymatic functions, and expanded target space. Here, we highlight important milestones and briefly discuss lessons learned about targeted protein degradation (TPD) in recent years and conjecture on the efforts still needed to expand the toolbox for PROTAC discovery to ultimately provide promising therapeutics.

中文翻译：

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PROTAC：过去、现在和未来

蛋白水解靶向嵌合体 (PROTAC) 是异双功能分子，由一个与目标蛋白 (POI) 结合的配体和另一个可以招募 E3 泛素连接酶的配体组成。POI 和 E3 连接酶之间化学诱导的接近导致 POI 泛素化，并随后被泛素蛋白酶体系统 (UPS) 降解。与传统的占据驱动小分子抑制剂相比，PROTAC 的事件驱动作用机制 (MOA) 具有多种优势，例如催化性质、减少给药和给药频率、更有效和更持久的作用、增加了一层降低潜在毒性的选择性、面对耐药机制的功效、针对非酶功能以及扩大的靶点空间。这里，