title: Structural biology contributions to tyrosine kinase drug discovery.
abstract: Successful kinase inhibitor drug discovery relies heavily on the structural knowledge of the interaction of inhibitors with the target. Structural biology of kinases and in particular of tyrosine kinases has given detailed insights into the intrinsic flexibility of the catalytic domain and has provided a rational basis for obtaining selective inhibitors. Important progress has been made recently, both in academia and in the pharmaceutical industry, with respect to solving structures of inactive, multidomain or protein-protein complexes of kinases, which helps our understanding of the dynamics of regulation of kinase activity. This leads to a better understanding of how mutations lead to activation of kinases and resistance, in addition to providing opportunities for novel modes of targeting kinases.
authors.affiliation: Novartis Institutes of Biomedical Research, Novartis Pharma AG, Postfach, Basel, Switzerland. sandra.jacob@novartis.com
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Henrik
authors.initials: H
authors.lastname: Möbitz
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D055808:Drug Discovery; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases