An unexpected chemical approach for engineering compounds that interact with their target via a reversible covalent mechanism is reported this week in Nature Chemical Biology.
Covalent drugs - which are used to treat many diseases including cancer - often interact with a particular amino acid residue in protein targets in a highly specific fashion and are irreversible so they can yield long-lasting effects. Some classes of covalent drugs are known to react with proteins in cells that are not the intended target, and these “off-target” interactions are also long lasting and can have detrimental consequences.
Jack Taunton and colleagues report a chemical approach to convert one common class of covalent drugs called acrylamides into reversible inhibitors. They demonstrate the utility of this approach by converting an irreversible covalent inhibitor for the kinase RSK2-important for cell division, growth and survival-into a reversible inhibitor. This chemical strategy may retain the specificity advantages gained through the covalent targeting of a certain amino acid residue while decreasing the potential negative consequences of irreversible off-target drug activity.
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