51. Reactive chemistry for covalent probe and therapeutic development.
- Author
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Grams, R. Justin and Hsu, Ku-Lung
- Subjects
- *
SMALL molecules , *PHARMACEUTICAL chemistry , *DRUG efficacy , *PROTEOMICS - Abstract
Bioactive small molecules that form covalent bonds with a target protein are important tools for basic research and can be highly effective drugs. This review highlights reactive groups found in a collection of thiophilic and oxophilic drugs that mediate pharmacological activity through a covalent mechanism of action (MOA). We describe the application of advanced proteomic and bioanalytical methodologies for assessing selectivity of these covalent agents to guide and inspire the search for additional electrophiles suitable for covalent probe and therapeutic development. While the emphasis is on chemistry for modifying catalytic serine, threonine or cysteine residues, we devote a substantial fraction of the review to a collection of exploratory reactive groups of understudied residues on proteins. Covalent drugs offer distinct advantages including high biochemical efficiency via nonequilibrium blockade, pharmacological activity that can outlast drug pharmacokinetics, and pharmacological access to 'undruggable' protein targets. While many covalent drugs were discovered serendipitously, recent examples of targeted covalent inhibitors (TCIs) in clinical use or testing support a path toward rational development. Advances in synthetic chemistry, proteomic screening, and bioanalytical instrumentation have enabled evaluation and medicinal chemistry optimization of covalent small molecule selectivity at an unprecedented scale. The development of reactive groups for modifying protein sites beyond catalytic serine, threonine, or cysteine residues offers great potential for expanding the scope of covalent probe and therapeutic discovery. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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