Recent Advances in the Structure-Guided Design of Protein Kinase Inhibitors
Pp. 145-170 (26)
The successful approval and launch of several small molecule protein kinase inhibitor drugs has stimulated further interest and research into therapeutics targeting kinases implicated in disease pathways. The use of protein structural information obtained from the kinase catalytic domain or substrate binding site has and continues to play a major role in the discovery and optimization of novel pharmacophores. A summary of progress made recently in the development of new structure based approaches for the discovery of kinase inhibitors is described. In addition, a number of case studies are presented demonstrating successful application of structure-guided design methods to the development of selective inhibitors targeting the cyclin dependent kinases, MAP kinases, and receptor tyrosine kinases. Inhibitors that preferentially bind to inactive kinase conformations are also covered as an area of recent exciting developments. In addition, the development of a new generation of selective kinase inhibitor drugs through targeting alternate binding sites distinct from the ATP cleft is presented.