Mechanism of action of erbB tyrosine kinase inhibitors

Over the last decade, drug discovery efforts have generated a myriad of compounds that inhibit the activity of the erbB family of tyrosine kinases with potencies and selectivity that have surpassed original expectations. These characteristics, along with improved pharmaceutical properties, have enabled inhibitors from this class of agents to finally realize their therapeutic potential, and indeed, some are currently producing significant clinical responses. Interestingly, those properties that are essential for a clinically active inhibitor of the erbB family are most readily attained with compounds that bind at the ATP site, and the most successful compounds have shown a distinct convergence to certain common chemical features. The reasons for this trend are beginning to be realized through the generation of an increasing array of crystalline structures for protein kinases as well as advances in molecular modeling. This has allowed a more complete understanding of the precise physical interactions that occur between erbB tyrosine kinase inhibitors and their target(s), which, in turn, has begun to shed light on the mechanism by which these molecules attain their remarkable affinity and specificity.