Unknown

Dataset Information

0

2-Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles.


ABSTRACT: The emerging use of covalent ligands as chemical probes and drugs would benefit from an expanded repertoire of cysteine-reactive electrophiles for efficient and diverse targeting of the proteome. Here we use the endogenous electrophile sensor of mammalian cells, the KEAP1-NRF2 pathway, to discover cysteine-reactive electrophilic fragments from a reporter-based screen for NRF2 activation. This strategy identified a series of 2-sulfonylpyridines that selectively react with biological thiols via nucleophilic aromatic substitution (SNAr). By tuning the electrophilicity and appended recognition elements, we demonstrate the potential of the 2-sulfonylpyridine reactive group with the discovery of a selective covalent modifier of adenosine deaminase (ADA). Targeting a cysteine distal to the active site, this molecule attenuates the enzymatic activity of ADA and inhibits proliferation of lymphocytic cells. This study introduces a modular and tunable SNAr-based reactive group for targeting reactive cysteines in the human proteome and illustrates the pharmacological utility of this electrophilic series.

SUBMITTER: Zambaldo C 

PROVIDER: S-EPMC7365253 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC10111338 | biostudies-literature
| S-EPMC6158072 | biostudies-literature
| S-EPMC3805131 | biostudies-literature
| S-EPMC2556149 | biostudies-literature
| S-EPMC10265533 | biostudies-literature
| S-EPMC5339396 | biostudies-literature
| S-EPMC6368244 | biostudies-literature
| S-EPMC5209257 | biostudies-literature
| S-EPMC10525603 | biostudies-literature
| S-EPMC4592840 | biostudies-literature