Vinyl Sulfones

Vinyl sulfones and sulfonamides are among the most common and efficient Michael acceptors and are good alternatives to acrylamides. This class of covalent binders attracted much attention with several representatives being in different stages of clinical trials. The recent investigation described by Adam Gilbert and co-workers using N-acetyl lysine and glutathione showed that vinyl sulfonyl derivatives in general are more reactive than acrylamides and sulfones are more active over sulfonamides. Last but not least vinyl sulfone and vinyl sulfonamide warheads displayed some selectivity toward Lys over cysteine residue if compared to popular acrylamide electrophiles.

Several recent examples of successful application of vinyl sulfones in drug discovery include irreversible protease inhibitor K11777 targeting noncatalytic Cys25, the first irreversible ATP-competitive inhibitor of CDK2 NU6300 targeting Lys89, FT827 potent covalent inhibitor of USP7 and promising SARS-CoV-2 Main protease inhibitor which covalently binds to Cys145.