ATP site-directed competitive and irreversible inhibitors of protein kinases

Several tyrosine and serine/threonine protein kinases have emerged in the last few years as attractive targets in the search for new therapeutic agents being applicable in many different disease indications. Initially, inhibition of these protein kinases by ATP site-directed inhibitors was considered less prone to success, but medicinal chemists from both academia and industry have been able to impart potency and selectivity to a limited number of scaffolds by modulating and fine-tuning the interactions of the modified template with the ATP binding site of the selected kinase. The chemical templates that have been used in the synthesis of ATP site-directed protein kinase inhibitors are reviewed with emphasis on the kinase inhibitors that have entered or are about to enter clinical trials. Examples have been selected to illustrate how structure-based design approaches and new methods to increase compound diversity have had an impact on this area of research.