Targeted protein degradation using thalidomide and its derivatives

抄録

Thalidomide, a small-molecule drug, caused a global drug disaster more than half a century ago. Thalidomide derivatives are widely used to treat several hematological cancers. Recent studies have revealed that thalidomide and its derivatives act as protein degraders that bind to cereblon (CRBN), the substrate-recognition receptor of a complex-type E3 ubiquitin ligase, and degrade neo-substrates that are not their original substrates. Furthermore, they are currently being used in proteolysis-targeting chimeras (PROTACs), which are chimeric protein degraders. Protein degraders open up a new mechanism of drug action and proteolysis and have the potential to target various therapeutic proteins, including undruggable proteins. Analysis of drug-dependent protein-protein interactions (PPIs) is crucial for the development and use of this new class of protein degraders. We developed an in vitro and intracellular protein degrader-dependent PPI analysis method using a cell-free protein synthesis system and proximity-dependent biotinylation. Using these analytical methods, we successfully identified several neo-substrates involved in the mechanism of action of thalidomide. Furthermore, we developed thalidomide derivatives and PROTACs with enhanced selectivity for neo-substrates or target proteins involved in the anti-hematological cancer effects. In this paper, we review the history of thalidomide and the research achievements related to protein degraders, as represented by thalidomide derivatives.