Targeted protein degradation (TPD) has greatly advanced as a therapeutic strategy in the past two decades, and we are on the cusp of rationally designed protein degraders reaching clinical approval. Offering pharmacological advantages relative to occupancy-driven protein inhibition, chemical methods for regulating biomolecular proximity have provided opportunities to tackle disease-related targets that were undruggable. Despite the pre-clinical success of designed degraders and existence of clinical therapies that serendipitously utilize TPD, expansion of the TPD toolbox is necessary to identify and characterize the next generation of molecular degraders. Here we highlight three areas for continued growth in the field that should be prioritized: expansion of TPD platform with greater spatiotemporal precision, increased throughput of degrader synthesis, and optimization of cooperativity in chemically induced protein complexes. The future is bright for TPD in medicine, and we expect that innovative approaches will increase therapeutic applications of proximity-induced pharmacology.

中文翻译：

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靶向蛋白降解的后续步骤


在过去的二十年里，靶向蛋白质降解 （TPD） 作为一种治疗策略取得了长足的进步，我们正处于合理设计的蛋白质降解剂获得临床批准的风口浪尖。与占位驱动的蛋白质抑制相比，调节生物分子邻近性的化学方法具有药理学优势，为处理不可成药的疾病相关靶点提供了机会。尽管设计的降解剂取得了临床前成功，并且存在偶然利用 TPD 的临床疗法，但有必要扩展 TPD 工具箱以识别和表征下一代分子降解剂。在这里，我们强调了该领域应优先考虑的三个持续增长领域：以更高的时空精度扩展 TPD 平台，提高降解剂合成的通量，以及优化化学诱导蛋白质复合物中的协同性。TPD 在医学领域的前景一片光明，我们预计创新方法将增加邻近诱导药理学的治疗应用。