Targeted protein degradation (TPD) revolutionizes drug discovery by taking advantages of event-driven mechanism of action (MOA). Among current proximity-inducing platforms for TPD, molecular glue degraders and proteol...Targeted protein degradation (TPD) revolutionizes drug discovery by taking advantages of event-driven mechanism of action (MOA). Among current proximity-inducing platforms for TPD, molecular glue degraders and proteolysis-targeting chimeras (PROTACs) are representative strategies that facilitate interactions between an E3 ligase and a specific protein target. This leads to ubiquitination and subsequent degradation of the target by the ubiquitin–proteasome system (UPS). Despite offering unprecedented opportunities for more effective and targeted therapies, current UPS-hijacking TPD still faces key challenges. For instance, although over 600 E3 ligases have been identified in human cells, only a handful, such as cereblon (CRBN) and von Hippel-Lindau (VHL), are accessible for developing degraders1. In addition, there are ongoing questions about how to further expand the chemically tractable target space beyond monomeric proteins with cytosolic domains.展开更多
文摘Targeted protein degradation (TPD) revolutionizes drug discovery by taking advantages of event-driven mechanism of action (MOA). Among current proximity-inducing platforms for TPD, molecular glue degraders and proteolysis-targeting chimeras (PROTACs) are representative strategies that facilitate interactions between an E3 ligase and a specific protein target. This leads to ubiquitination and subsequent degradation of the target by the ubiquitin–proteasome system (UPS). Despite offering unprecedented opportunities for more effective and targeted therapies, current UPS-hijacking TPD still faces key challenges. For instance, although over 600 E3 ligases have been identified in human cells, only a handful, such as cereblon (CRBN) and von Hippel-Lindau (VHL), are accessible for developing degraders1. In addition, there are ongoing questions about how to further expand the chemically tractable target space beyond monomeric proteins with cytosolic domains.
