Targeted protein degradation: drug discovery opportunities & resistance mechanisms
Institute for Research in Biomedicine (IRB Barcelona)
Targeted protein degradation is a pharmacological strategy based on drugs (degraders) that destabilize proteins by hijacking the intracellular proteolysis machinery. This strategy has garnered significant attention in the last year owing to its potential to modulate the abundance of proteins that are difficult to target with conventional inhibitors. Degraders can be multivalent (PROTACs) or monovalent (molecular glue degraders) depending on the number of chemical warheads. Molecular glue degraders orchestrate direct interactions between a target protein and an E3 ubiquitin ligase, prompting target ubiquitination and subsequent proteasomal degradation. They have incredible therapeutic potential, particularly considering delivering on the promise of degrading otherwise “undruggable” proteins. However, their discovery has thus far been largely serendipitous. A scalable strategy to identify them based on differential chemical profiling will be discussed. In addition, we and others have mapped the genetic determinants governing degrader efficiency, bringing important lessons about potential resistance mechanisms. A chemoproteomics journey to deliver strategies that overcome resistance to degraders will be shown.