Cereblon E3 Ligase Pathway

The Cereblon E3 ligase pathway is a protein degradation pathway centered around the Cereblon (CRBN) protein, a substrate receptor within the CRL4^CRBN E3 ubiquitin ligase complex. This complex mediates the ubiquitination and subsequent proteasomal degradation of target proteins, regulating various cellular processes. The pathway is a key therapeutic target, particularly through the use of immunomodulatory imide drugs (IMiDs) that bind to cereblon and redirect its activity to degrade disease-relevant proteins. The pathway plays roles in multiple myeloma, myelodysplastic syndrome and other immunologic conditions. The pathway is also being leveraged for next-generation therapeutics such as PROTACs that use synthetic ligands targeting CRBN for induced proximity-mediated target degradation.

IMiDs bind to cereblon, altering its substrate specificity and leading to the ubiquitination and degradation of neosubstrates.