Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada; Department of Chemistry, University of Toronto, Toronto, ON, Canada.
Department of Chemical and Physical Sciences, University of Toronto Mississauga, Mississauga, ON, Canada.
Methods Cell Biol. 2022;169:1-26. doi: 10.1016/bs.mcb.2022.01.001. Epub 2022 Mar 31.
Targeted protein degradation has emerged as a transformative therapeutic modality for the treatment of human diseases. The clinical successes of approved protein degraders like lenalidomide and thalidomide in cancers and immune disorders, combined with the recent clinical debut of investigational heterobifunctional degraders, have demonstrated the potential of this pharmacological approach to expand the druggable proteome and improve patient outcomes. Molecular glue degraders are a class of protein degraders that operate by recruiting target proteins to cellular degradation machinery via noncanonical protein-protein interactions, inducing the destruction of the target protein. While heterobifunctional degraders consist of two distinct protein-binding moieties connected by a linker, molecular glue degraders contain a single pharmacophore and are thus more synthetically accessible, ligand-efficient, and often possess more drug-like physicochemical properties. In this chapter, we will explore the history of the field-from its conception to the recently accelerating discovery of novel glue degrader mechanisms-and contemplate its trajectory towards rational design with the emergence of new methods for protein quantification and high-throughput assays to screen for novel degraders.
靶向蛋白降解已成为治疗人类疾病的一种变革性治疗模式。已批准的蛋白降解剂(lenalidomide 和 thalidomide)在癌症和免疫疾病中的临床成功，加上最近研究性杂双功能降解剂的临床应用，证明了这种药物方法有潜力扩大可成药蛋白质组并改善患者的预后。分子胶降解剂是一类蛋白降解剂，通过非典型的蛋白-蛋白相互作用将靶蛋白招募到细胞降解机制中，从而诱导靶蛋白的破坏。虽然杂双功能降解剂由通过连接子连接的两个不同的蛋白结合部分组成，但分子胶降解剂仅包含一个药效团，因此更具合成可及性、配体效率更高，并且通常具有更多类药性的物理化学性质。在本章中，我们将探讨该领域的历史——从其概念的提出到最近新型胶降解机制的加速发现，并考虑随着新的蛋白质定量方法和高通量筛选新型降解剂的检测方法的出现，其向合理设计的发展轨迹。
