Classic small molecule inhibitors that directly target pathogenic proteins typically rely on the accessible binding sites to achieve prolonged occupancy and influence protein functions. The emerging targeted protein degradation (TPD) strategies exemplified by PROteolysis TArgeting Chimeras (PROTACs) are revolutionizing conventional drug discovery modality to target proteins of interest (POIs) that were categorized as “undruggable” before, however, these strategies are limited within intracellular POIs. The novel new degrader technologies such as LYsosome-TArgeting Chimaeras (LYTACs) and Antibody-based PROTACs (AbTACs) have been successfully developed to expand the scope of TPD to extracellular and membrane proteins, fulfilling huge unmet medical needs. Here, we systematically review the currently viable protein degradation strategies, emphasize that LYTACs and AbTACs turn a new avenue for the development of TPD, and highlight the potential challenges and directions in this vibrant field.

中文翻译：

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新兴的蛋白质降解策略：将范围扩展到细胞外和膜蛋白

直接靶向致病蛋白的经典小分子抑制剂通常依赖于可接近的结合位点来实现长时间的占用并影响蛋白质功能。以蛋白水解靶向嵌合体 (PROTACs) 为代表的新兴靶向蛋白质降解 (TPD) 策略正在彻底改变传统的药物发现模式，以靶向以前被归类为“不可治疗”的感兴趣的蛋白质 (POI)，然而，这些策略仅限于细胞内 POI。成功开发了溶酶体靶向嵌合体（LYTACs）和基于抗体的PROTACs（AbTACs）等新型降解技术，将TPD的范围扩展到细胞外和膜蛋白，满足了巨大的未满足的医疗需求。在这里，我们系统地回顾了目前可行的蛋白质降解策略，