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PROTACs (proteolysis targeting chimeras) are hybrid molecules that promote co-localisation of a target protein and cereblon (CRBN) to promote E3 ligase CRL4CRBN-mediated ubiquitination and proteasomal degradation of the chosen target protein [1]. PROTACs effectively remove specific proteins from within cells, and offer therapeutic potential beyond traditional small molecule inhibitors. Molecular 'glues' use a different mechanism. They employ a single interaction with cereblon [2], and via this interaction they alter the substrate specificity of the E3 ligase, so that neo-substrates are targeted for proteasomal degradation. The immunomodulatory imide drug (iMiD) thalidomide and its analogues are the archetypal 'glues'.
Database page citation:
PROTACs and molecular glues. Accessed on 16/01/2021. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1030.