Abstract
Protein kinases are obvious drug targets against cancer due to their central role in cellular regulation. With oncologic diseases being the second leading cause of death in the US kinases rapidly gain attention and are likely to become the number one drug target. Using NMR and fast kinetics, we establish a novel model that solves a longstanding question of high selectivity of clinically relevant drug Gleevec that effectively inhibits Abl tyrosine kinase while closely related Src family of kinases is affected much less. Our study of an entirely different family of Ser/Thr Aurora kinases and its specific inhibitors suggests that an energy landscape that provides tight affinity via an induced-fit and binding plasticity via a conformational selection mechanism is likely to be general for many inhibitors.
