Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators.
RSC Med Chem
; 15(2): 607-611, 2024 Feb 21.
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| ID: mdl-38389883
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 CRL4CRBN. 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 via the advancement of medicinal chemistry design strategies.
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01-internacional
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MEDLINE
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En
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RSC Med Chem
Año:
2024
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Article