Covalent Stapling of the Cereblon Sensor Loop Histidine Using Sulfur-Heterocycle Exchange.

ABSTRACT: Site-specific modification of amino acid residues in protein binding pockets using sulfonyl exchange chemistry expands the druggable proteome by enabling the development of covalent modulators that target residues beyond cysteine. Sulfonyl fluoride and triazole electrophiles were incorporated previously into the cereblon (CRBN) molecular glue degrader EM12, to covalently engage His353 within the CRBN sensor loop, but these probes had poor human plasma stability. Attenuation of intrinsic reactivity through the development of sulfonyl pyrazoles, imidazoles, and nucleobases enhanced plasma stability, and several compounds retained efficient labeling of His353. For example, sulfonyl imidazole EM12-SO₂Im covalently blocked the CRBN binding site and possessed excellent metabolic stabi

SUBMITTER: Cruite JT 

PROVIDER: S-EPMC10641907 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature