2‑Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles

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.