{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["15(2)"],"submitter":["Liu Y"],"pubmed_abstract":["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<sup>CRBN</sup>. 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."],"journal":["RSC medicinal chemistry"],"pagination":["607-611"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10880902"],"repository":["biostudies-literature"],"pubmed_title":["Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators."],"pmcid":["PMC10880902"],"pubmed_authors":["Liu H","Liu Y","Nowak RP","Jones LH","Donovan KA","Che J","Metivier RJ","Huerta F","Fischer ES"],"additional_accession":[]},"is_claimable":false,"name":"Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators.","description":"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<sup>CRBN</sup>. 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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Feb","modification":"2026-06-02T00:10:07.225Z","creation":"2026-05-24T03:07:42.25Z"},"accession":"S-EPMC10880902","cross_references":{"pubmed":["38389883"],"doi":["10.1039/d3md00652b"]}}