Energetic dissection of Gleevec’s selectivity towards human tyrosine kinases

Protein kinases are obvious drug targets against cancer due to their central role in cellular regulation. Since the discovery of Gleevec, a potent and specific inhibitor of Abl kinase, as a highly successful cancer therapeutic, the ability of this drug to distinguish between Abl and other tyrosine kinases like Src has been intensely investigated, but without much success. Using NMR and fast kinetics, we establish a novel model that solves this longstanding question of two tyrosine kinases adopting almost identical structures when bound to Gleevec, yet having vastly different affinities. In contrast to all other proposed models we show that the origin of Abl’s high affinity lies predominantly in a conformational change after binding. An energy landscape that provides tight affinity via an induced-fit and binding plasticity via conformational selection mechanism is likely to be general for many inhibitors.