biostudies-literatureAlmodovar-Rivera CMNational Institute of General Medical Sciences of the National Institutes of HealthWisconsin Alumni Research FoundationWisconsin Alumni Research Foundation (WARF)NCI NIH HHSNational Institutes of HealthLachman Institute for Pharmaceutical Development and UW Carbone Cancer CenterNIGMS NIH HHSNIH HHSe202500209https://www.ebi.ac.uk/biostudies/studies/S-EPMC12471865biostudies-literatureUnknown20(22)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 PROTChemMedChemDevelopment of a Partial Proteolysis Targeting Chimera Library Based on Achiral Cereblon E3 Ligase Ligands and its Application for Bruton's Tyrosine Kinase Degraders.PMC12471865R35GM148266UW2020T32 GM141013NIH P30 CA014520T32 GM152341T32GM152341P30 CA014520R35 GM148266Tandon IMudududdla REsguerra PNTang WAlmodovar-Rivera CMLucio-Acero KfalseDevelopment of a Partial Proteolysis Targeting Chimera Library Based on Achiral Cereblon E3 Ligase Ligands and its Application for Bruton's Tyrosine Kinase Degraders.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 PROT2025-01-01T00:00:00Z2025 Nov2026-06-06T13:43:12.77Z2026-05-31T03:09:51.334ZS-EPMC124718654096341610.1002/cmdc.202500209