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2‑Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles
journal contribution
posted on 2020-04-29, 16:03 authored by Claudio Zambaldo, Ekaterina V. Vinogradova, Xiaotian Qi, Jonathan Iaconelli, Radu M. Suciu, Minseob Koh, Kristine Senkane, Stormi R. Chadwick, Brittany B. Sanchez, Jason S. Chen, Arnab K. Chatterjee, Peng Liu, Peter G. Schultz, Benjamin F. Cravatt, Michael J. BollongThe 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.
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Keywords
recognition elementsNRF 2 activationcysteine-reactive electrophilesmolecule attenuatesKEAP 1-NRF pathwaycovalent modifier2- sulfonylpyridineselectrophilic seriesS N Arproteomereactive cysteinesadenosine deaminasechemical probescysteine-reactive electrophilic fragmentselectrophile sensortunable S N Ar-based reactive groupCysteine-Reactive ElectrophilesADA2- sulfonylpyridine reactive groupcovalent ligandsreporter-based screen