ATP site-directed competitive and irreversible inhibitors of protein kinases

Several tyrosine and serine/threonine protein kinases have emerged in the l ast few years as attractive targets in the search for new therapeutic agent s being applicable in many different disease indications. Initially, inhibi tion of these protein kinases by ATP site-directed inhibitors was considere d less prone to success, but medicinal chemists from both academia and indu stry have been able to impart potency and selectivity to a limited number o f scaffolds by modulating and fine-tuning the interactions of the modified template with the ATP binding site of the selected kinase. The chemical tem plates that have been used in the synthesis of ATP site-directed protein ki nase inhibitors are reviewed with emphasis on the kinase inhibitors that ha ve entered or are about to enter clinical trials. Examples have been select ed to illustrate how structure-based design approaches and new methods to i ncrease compound diversity have had an impact on this area of research. (C) 2000 John Wiley & Sons, Inc.