biostudies-literatureUnknown15(2)Liu YSulfonyl fluoride EM12-SF was developed previously to covalently engage a histidine residue in the sensor loop of cereblon (CRBN) in the E3 ubiquitin ligase complex CRL4^CRBN. Here, we further develop the structure-activity relationships of additional sulfonyl fluoride containing ligands that possess a range of cereblon binding potencies in cells. Isoindoline EM364-SF, which lacks a key hydrogen bond acceptor present in CRBN molecular glues, was identified as a potent binder of CRBN. This led to the development of the reversible molecular glue CPD-2743, that retained cell-based binding affinity for CRBN and degraded the neosubstrate IKZF1 to the same extent as EM12, but unlike isoindolinones, lacked SALL4 degradation activity (a target linked to teratogenicity). CPD-2743 had high permeability and lacked efflux in Caco-2 cells, in contrast to the isoindolinone iberdomide. Our methodology expands the repertoire of sulfonyl exchange chemical biology <i>via</i> the advancement of medicinal chemistry design strategies.RSC medicinal chemistry607-611https://www.ebi.ac.uk/biostudies/studies/S-EPMC10880902biostudies-literatureDevelopment of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators.PMC10880902Liu HLiu YNowak RPJones LHDonovan KAChe JMetivier RJHuerta FFischer ESfalseDevelopment of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators.Sulfonyl fluoride EM12-SF was developed previously to covalently engage a histidine residue in the sensor loop of cereblon (CRBN) in the E3 ubiquitin ligase complex CRL4^CRBN. Here, we further develop the structure-activity relationships of additional sulfonyl fluoride containing ligands that possess a range of cereblon binding potencies in cells. Isoindoline EM364-SF, which lacks a key hydrogen bond acceptor present in CRBN molecular glues, was identified as a potent binder of CRBN. This led to the development of the reversible molecular glue CPD-2743, that retained cell-based binding affinity for CRBN and degraded the neosubstrate IKZF1 to the same extent as EM12, but unlike isoindolinones, lacked SALL4 degradation activity (a target linked to teratogenicity). CPD-2743 had high permeability and lacked efflux in Caco-2 cells, in contrast to the isoindolinone iberdomide. Our methodology expands the repertoire of sulfonyl exchange chemical biology <i>via</i> the advancement of medicinal chemistry design strategies.2024-01-01T00:00:00Z2024 Feb2026-06-02T00:10:07.225Z2026-05-24T03:07:42.25ZS-EPMC108809023838988310.1039/d3md00652b