biostudies-literatureNie XUniversity of Wisconsin Carbone Cancer CenterNCI NIH HHSNational Institutes of HealthNIH HHSNIGMS NIH HHSe202300685https://www.ebi.ac.uk/biostudies/studies/S-EPMC10922875biostudies-literatureUnknown25(4)Thalidomide, pomalidomide and lenalidomide, collectively referred to as immunomodulatory imide drugs (IMiDs), are frequently employed in proteolysis-targeting chimeras (PROTACs) as cereblon (CRBN) E3 ligase-recruiting ligands. However, their molecular glue properties that co-opt the CRL4^CRBN to degrade its non-natural substrates may lead to undesired off-target effects for the IMiD-based PROTAC degraders. Herein, we reported a small library of potent and cell-permeable CRBN ligands, which exert high selectivity over the well-known CRBN neo-substrates of IMiDs by structure-based design. They were further utilized to construct bromodomain-containing protein 4 (BRD4) degraders, which successfully depleted BRD4 in the tested cells. Overall, we reported a series of functionalized CRBChembiochem : a European journal of chemical biologyDevelopment of Phenyl-substituted Isoindolinone- and Benzimidazole-type Cereblon Ligands for Targeted Protein Degradation.PMC10922875R35GM148266NIH P30 CA014520R01 GM137090R01 GM137090P30 CA014520R35 GM148266T32 GM008505Wang BGuan HXing YSundaresan RZhao YTang HLiao JGuo LZhang ZXie HTang WNie XAlmodovar-Rivera CMfalseDevelopment of Phenyl-substituted Isoindolinone- and Benzimidazole-type Cereblon Ligands for Targeted Protein Degradation.Thalidomide, pomalidomide and lenalidomide, collectively referred to as immunomodulatory imide drugs (IMiDs), are frequently employed in proteolysis-targeting chimeras (PROTACs) as cereblon (CRBN) E3 ligase-recruiting ligands. However, their molecular glue properties that co-opt the CRL4^CRBN to degrade its non-natural substrates may lead to undesired off-target effects for the IMiD-based PROTAC degraders. Herein, we reported a small library of potent and cell-permeable CRBN ligands, which exert high selectivity over the well-known CRBN neo-substrates of IMiDs by structure-based design. They were further utilized to construct bromodomain-containing protein 4 (BRD4) degraders, which successfully depleted BRD4 in the tested cells. Overall, we reported a series of functionalized CRB2024-01-01T00:00:00Z2024 Feb2026-06-01T12:59:32.544Z2025-04-04T01:11:53.927ZS-EPMC109228753811685410.1002/cbic.202300685