Overview
PROTACs (proteolysis targeting chimeras) are hybrid molecules that promote co-localisation of a target protein and E3 ligase recruiters such as cereblon (CRBN) to promote E3 ligase-mediated ubiquitination and proteasomal degradation of the chosen target protein [2]. PROTACs effectively remove specific proteins from within cells, and offer therapeutic potential beyond traditional small molecule inhibitors. Molecular 'glues' use a different mechanism. They are monovalent small molecules, that employ a single interaction with an E3 ligase recruiter, and this alters the substrate specificity of the E3 ligase, so that neo-substrates are targeted for proteasomal degradation [3]. The immunomodulatory imide drug (iMiD) thalidomide and its analogues are the archetypal 'glues'. Work is ongoing to uncover additional druggable E3 ligases [1].
Ligands
Further reading
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PROTACs, molecular glues and other degraders. Accessed on 20/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1030.
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