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Targeting cancer with small molecule irreversible inhibitors of kinases represents an emerging challenge in drug discovery. Irreversible inhibitors bind to kinase active site in a covalent and irreversible form, most frequently by reacting with a nucleophilic cysteine residue, located near the ATP binding pocket. The most common mechanism is the Michael reaction, that refers to the addition of a nucleophile, such as cysteine, to an α,β-unsaturated carbonyl. The nucleophile reacts at the electrophilic β-position to form an adduct; as a result the inhibitor irreversibly blocks binding of ATP to the kinase, rendering the kinase inactive. Different cysteine-reactive groups have been evaluated, an acrylamide or a substituted acrylamide moiety are the Michael acceptors of choice. There are some advantages for the irreversible kinase inhibition. These compounds are highly selective because they target a specific cysteine and …