From Thalidomide to Rational Molecular Glue Design for Targeted Protein Degradation

Annu Rev Pharmacol Toxicol. 2023 Aug 16. doi: 10.1146/annurev-pharmtox-022123-104147. Online ahead of print.ABSTRACTThalidomide and its derivatives are powerful cancer therapeutics that are among the best-understood molecular glue degraders (MGDs). These drugs selectively reprogram the E3 ubiquitin ligase cereblon (CRBN) to commit target proteins for degradation by the ubiquitin-proteasome system. MGDs create novel recognition interfaces on the surface of the E3 ligase that engage in induced protein-protein interactions with neosubstrates. Molecular insight into their mechanism of action opens exciting opportunities to engage a plethora of targets through a specific recognition motif, the G-loop. Our analysis shows that current CRBN-based MGDs can in principle recognize over 2,500 proteins in the human proteome that contain a G-loop. We review recent advances in tuning the specificity between CRBN and its MGD-induced neosubstrates and deduce a set of simple rules that govern these interactions. We conclude that rational MGD design efforts will enable selective degradation of many more proteins, expanding this therapeutic modality to more disease areas. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.PMID:37585660 | DOI:10.1146/annurev-pharmtox-022123-104147
Source: Annual Review of Pharmacology and Toxicology - Category: Drugs & Pharmacology Authors: Source Type: research