Inhibitors of PKA and Related Protein Kinases

Abstract

The AGC group of protein kinases comprises a number of pharmacologically important members—targets for small molecule inhibitors of therapeutic value. Crystal structure data assist in the design of new or improved inhibitory molecules. Protein kinase A (PKA), one of the longest and best-known members of the AGC kinase group, has been cocrystallized with many AGC group inhibitors from highly diverse chemical groups, including isoquinoline derivatives, staurosporine and bisindolylmaleimide cognates, and balanol and pyridine derivatives, thus providing structural information about binding modes, selectivity and cross selectivity. The creation of ‘ersatz’ kinases by mutating the inhibitor binding site of PKA to resemble other fellow kinases from the AGC group and the cocrystallization of these ersatz kinases with small molecules as well as cocrystal structures of other AGC kinases like 3-phosphoinositide-dependent kinase 1 (PDK1) with staurosporine and bisindolylmaleimide derivatives helps in the identification and exploration of factors governing selectivity.