Abstract: DNA-encoded library (DEL) technology enables the identification of new ligands which engage a desired protein target, supporting an essential step of any early drug discovery program. Covalent target engagement is gaining traction in the small-molecule therapeutic space, however approaches to identify novel covalent ligands are still emerging. To this end, we synthesized multiple DNA-encoded chemical libraries terminated in electrophiles and then used them to discover covalent irreversible inhibitors and report the successful discovery of acrylamide- and epoxide-terminated Bruton’s Tyrosine Kinase (BTK) inhibitors. We also demonstrate their selectivity, potency and covalent cysteine engagement using a range of techniques including X-ray crystallography, thermal transition shift assay, reporter displacement assay and intact protein complex mass spectrometry. The application of DEL screening towards the identification of protein-protein interactions modulators is another area of active interest which will be discussed.
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