A Degron Blocking Strategy Towards Improved CRL4CRBN Recruiting PROTAC Selectivity

E3 ligase mediated targeted protein degradation is an ever more important area in drug discovery. In the case of cereblon two avenues exist; either heterobifunctional PROTACs, or discrete cereblon ligands that induce a specific neosubstrate degron association to the complex. Here we present a degron blocking approach, whereby structural and in silico understandings of degron association has directed ligand design to block IMiD-like binding of degron containing neosubstrates, thus enhancing PROTAC selectivity. More information can be found in the Research Article by H. Bouguenina, J. J. Caldwell et al.