PROTACs (proteolysis targeting chimeras) are hybrid molecules that promote co-localisation of a target protein and cereblon (CRBN) to promote E3 ligase CRL4^CRBN-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'.

1. Churcher I. (2018) Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones?. J. Med. Chem., 61 (2): 444-452. [PMID:29144739]

2. Heim C, Pliatsika D, Mousavizadeh F, Bär K, Hernandez Alvarez B, Giannis A, Hartmann MD. (2019) De-Novo Design of Cereblon (CRBN) Effectors Guided by Natural Hydrolysis Products of Thalidomide Derivatives. J. Med. Chem., 62 (14): 6615-6629. [PMID:31251063]