Kinases are highly regulated enzymes with diverse mechanisms controlling their catalytic output. Inhibitor discovery efforts for kinases have produced ATP-competitive compounds, allosteric regulators, irreversible binders, and highly specific inhibitors.  These distinct classes of small molecules have revealed many novel aspects about kinase-mediated signaling and some have progressed from simple tool compounds into clinically validated therapeutics. A complete surprise of targeted kinase drug discovery has been discovery of ATP-competitive inhibitors that behave as agonists, rather than antagonists, of their direct kinase target. These studies hint at a connection between ATP binding site occupancy and networks of communication that are independent of kinase catalysis.  Indeed, kinase inhibitors have been found that induce changes in protein localization, protein-protein interactions, and even enhancement of catalytic activity of the target kinase.  The relevance of these findings to therapeutic efficacy of kinase inhibitors and to future identification of new classes of drug targets will be discussed.

Award Address (Ronald Breslow Award for Achievement in Biomimetic Chemistry sponsored by The Ronald Breslow Award Endowment). Chemical genetic investigations of protein and lipid kinase signaling

241st National Meeting (2011)

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