Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 27, Issue 15, Pages 3421-3439Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2019.05.050
Keywords
Covalent inhibitors; Cysteines; Kinase inhibitors; Phosphatase inhibitors; Protease inhibitors; Electrophiles; Chemoproteomics; Chemical immunology; Covalent immunomodulators
Funding
- David Geffen School of Medicine at UCLA
- UCLA Jonsson Comprehensive Cancer Center
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Compounds that react irreversibly with cysteines have reemerged as potent and selective tools for altering protein function, serving as chemical probes and even clinically approved drugs. The exquisite sensitivity of human immune cell signaling pathways to oxidative stress indicates the likely, yet still underexploited, general utility of covalent probes for selective chemical immunomodulation. Here, we provide an overview of immunomodulatory cysteines, including identification of electrophilic compounds available to label these residues. We focus our discussion on three protein classes essential for cell signaling, which span the 'druggability' spectrum from amenable to chemical probes (kinases), somewhat druggable (proteases), to inaccessible (phosphatases). Using existing inhibitors as a guide, we identify general strategies to guide the development of covalent probes for selected undruggable classes of proteins and propose the application of such compounds to alter immune cell functions.
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