Molecular Glues
Defining New Biology at the Intersection of Mitochondria and UPS
Mechanism of Molecular Glues
Mechanism of Molecular Glue-Induced Target Degradation
Figure 2. Molecular glues are small molecules that bind E3 ligases and induces a conformational change such that the E3 ligase can interact with a new target protein promoting its ubiquitination and subsequent degradation.
Therapeutic Promise of Molecular Glues
This mechanism has gained significant attention in targeted protein degradation (TPD), particularly in the development of therapies for cancer and other diseases involving undruggable or pathogenic proteins. One well-known example is the immunomodulatory imide drugs (IMiDs) like thalidomide and its derivatives, which bind to the cereblon E3 ligase complex and promote degradation of transcription factors such as Ikaros and Aiolos. Molecular glues offer a promising strategy for expanding the druggable proteome by leveraging the cell’s own degradation machinery.
