Recent advances in protein kinase inhibition: current molecular scaffolds used for inhibitor synthesis

Early efforts to discover and develop protein kinase inhibitors have focused largely on a small group of oncology targets such as the EGFR and PKC enzymes. More recently, hundreds of protein kinases have been identified at the genetic level, many of which are now being assigned functions in a variety of signaling pathways. Additionally, mutagenesis and X-ray crystallographic studies have further defined common structural features associated with binding of the ATP cofactor within a conserved ATP binding cleft. These studies have also demonstrated significant differences in the ATP binding cleft between individual kinases, providing a molecular basis for understanding and exploiting inhibitor specificity. The current review will focus on recent developments in the field of ATP site-directed inhibitors with particular emphasis on the major scaffolds being derivatized to take advantage of variable regions of the active site.