Monday, April 20, 2020

2-Sulfonyl pyridines as tunable, cysteine-reactive electrophiles [@mikebollong]

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, and Michael J. Bollong
Journal of the American Chemical Society, 2020
DOI: 10.1021/jacs.0c02721

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-sulfonyl pyridines that selectively react with biological thi-ols via nucleophilic aromatic substitution (SNAr). By tuning the electrophilicity and appended recognition elements, we demonstrate the potential of the 2-sulfonyl pyridine 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.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...