Structure based rules for protein kinase inhibitor selectivity

Protein kinase inhibitors are now emerging as a major class of new targeted drugs. Many diseases, especially cancers, are associated with disregulation of signalling pathways, and modulation of protein kinase activity is now a clearly validated approach f or therapy. Because there are over 500 protein kinases in the human genome (the "kinome"), and a multiple of this when considering splice variations, disease mutations, post-translational modifications, and mutiple protein complexes, selectivity of therap eutic inhibitors (or activators) is a key parameter for success. This research project, along the lines of chemogenomics, chemical biology, or systems biology attempts to address this complex issue in two key ways. On the one hand, a panel of protein kina ses will be established for high throughput tasks, including crystal structure determination, other biophysical studies, and ligand screening. These studies will generate knowledge of selectivity mechanisms for protein kinase inhibition, as well as new or modified inhibitors with distinct selectivity profiles. On the other hand, key protein kinase targets for therapeutic inhibitors, including especially PKC and also ABL, PKB, MK, Aurora, SRC, and others will be studied in detail, examining the role of spe cific side chains, phosphorylation, domain architecture, and protein-protein interactions in determining selectivity. Such detailed studies are required to validate the assumptions of high throughput strategies, which by necessity used simplified or stand ardized protocols for data generation. The project forms a network of Norwegian and international protein kinase experts and technology platforms with expertise ranging from clinical studies to theoretical chemistry, and includes key technologies of cell imaging, enzymatic screening, protein crystallography, ligand binding thermodynamics, and others.