The structure-based design of ATP-site directed protein kinase inhibitors

The protein kinase family represents both a huge opportunity and a challeng e for drug development. The conservation of structural features within the ATP binding cleft initially led to the belief that specificity would be dif ficult to achieve. This dogma has now been clearly dispelled with the disco very and clinical testing of a group of first generation compounds, which a re characterized by a high degree of selectivity towards a variety of oncol ogy targets. The structural basis for selectivity and potency has now been clarified with the crystallization of a number of such targets in complex w ith inhibitors. The protein kinase inhibitor field is now ripe for the stru cture based exploitation of additional highly validated targets from a vari ety of therapeutic areas.