Targeted protein degradation (TPD) has emerged in the past decade as a major new drug modality to remove intracellular proteins with bispecific small molecules that recruit the protein of interest (POI) to an E3 ligase for degradation in the proteasome. Unlike classic occupancy-based drugs, intracellular TPD (iTPD) eliminates the target and works catalytically, and so can be more effective and sustained, with lower dose requirements. Recently, this approach has been expanded to the extracellular proteome, including both secreted and membrane proteins. Extracellular targeted protein degradation (eTPD) uses bispecific antibodies, conjugates or small molecules to degrade extracellular POIs by trafficking them to the lysosome for degradation. Here, we focus on recent advances in eTPD, covering degrader systems, targets, molecular designs and parameters to advance them. Now almost any protein, intracellular or extracellular, is addressable in principle with TPD.

靶向蛋白质降解 (TPD) 在过去十年中已成为一种主要的新药物模式，通过双特异性小分子去除细胞内蛋白质，将目标蛋白质 (POI) 招募到 E3 连接酶中，以便在蛋白酶体中降解。与经典的基于占据的药物不同，细胞内 TPD (iTPD) 消除了靶标并起催化作用，因此可以更有效、更持久，且剂量要求更低。最近，这种方法已扩展到细胞外蛋白质组，包括分泌蛋白和膜蛋白。细胞外靶向蛋白降解 (eTPD) 使用双特异性抗体、缀合物或小分子通过将细胞外 POI 运输到溶酶体进行降解来降解它们。在这里，我们重点关注 eTPD 的最新进展，涵盖降解系统、靶标、分子设计和推进它们的参数。现在，几乎所有蛋白质，无论是细胞内还是细胞外，原则上都可以通过 TPD 进行寻址。