Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA.
Lachman Institute for Pharmaceutical Development, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705, USA; Department of Chemistry, University of Wisconsin-Madison, 1101 University Avenue, Madison, WI 53706, USA.
Trends Pharmacol Sci. 2023 Nov;44(11):762-775. doi: 10.1016/j.tips.2023.08.013. Epub 2023 Sep 25.
Targeted protein degradation (TPD) involving chimeric molecules has emerged as one of the most promising therapeutic modalities in recent years. Among various reported TPD strategies, proteolysis-targeting chimeras (PROTACs) stand out as a significant breakthrough in small-molecule drug discovery and have garnered the most attention to date. However, PROTACs are mainly capable of depleting intracellular proteins. Given that many important therapeutic targets such as cytokines, growth factors, and numerous receptors are membrane proteins or secreted extracellularly, there is interest in the development of novel strategies to degrade these protein categories. We review advances in this emerging area and provide insights to enhance the development of novel TPDs targeting extracellular proteins.
靶向蛋白降解（TPD）涉及嵌合分子，近年来已成为最有前途的治疗方式之一。在各种报道的 TPD 策略中，蛋白水解靶向嵌合体（PROTAC）在小分子药物发现方面取得了重大突破，迄今为止受到了最多的关注。然而，PROTAC 主要能够耗尽细胞内蛋白。鉴于许多重要的治疗靶点，如细胞因子、生长因子和众多受体，都是膜蛋白或分泌到细胞外，因此人们有兴趣开发新的策略来降解这些蛋白类别。我们综述了这一新兴领域的进展，并提供了一些见解，以促进针对细胞外蛋白的新型 TPD 的开发。
