The Structure-Based Design of ATP-Site Directed Protein KinaseInhibitors

The structure basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex with inhibitors and the structure based exploitation of additional highly validated targets from a variety of therapeutic areas is now ripe.

Abstract

The protein kinase family represents both a huge opportunity and a challenge for drug development. The conservation of structural features within the ATP binding cleft initially led to the belief that specificity would be difficult to achieve. This dogma has now been clearly dispelled with the discovery and clinical testing of a group of first generation compounds, which are characterized by a high degree of selectivity towards a variety of oncology targets. The structural basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex with inhibitors. The protein kinase inhibitor field is now ripe for the structure based exploitation of additional highly validated targets from a variety of therapeutic areas.