Open Access2-Sulfonylpyridines as Tunable, Cysteine-Reactive Electrophiles
Author(s) -
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. Bollong
Publication year - 2020
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.0c02721
Subject(s) - chemistry , electrophile , cysteine , nucleophilic aromatic substitution , reactive intermediate , nucleophile , small molecule , combinatorial chemistry , covalent bond , drug discovery , biochemistry , stereochemistry , enzyme , nucleophilic substitution , organic chemistry , catalysis
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 (S N Ar). 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 S N Ar-based reactive group for targeting reactive cysteines in the human proteome and illustrates the pharmacological utility of this electrophilic series.