Development of a Partial Proteolysis Targeting Chimera Library Based on Achiral Cereblon E3 Ligase Ligands and its Application for Bruton's Tyrosine Kinase Degraders.

ABSTRACT: Proteolysis targeting chimeras (PROTACs) offer a promising therapeutic approach by leveraging the ubiquitin-proteasome system (UPS) to degrade target proteins. These heterobifunctional molecules consist of a target protein ligand, an E3 ligase ligand, and a linker. Among the limited E3 ligase ligands available, cereblon (CRBN) ligands are the most widely used. However, the stability and racemization of current chiral CRBN ligands pose challenges for developing CRBN-recruiting PROTAC therapeutics. Herein, a partial PROTAC library is reported incorporating an aldehyde motif and various linkers into previously developed achiral phenyl dihydrouracil CRBN ligands, which offer improved stability and eliminate racemization issues. This library enables the rapid generation of fully functional PROT

SUBMITTER: Almodovar-Rivera CM 

PROVIDER: S-EPMC12471865 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature