title: High throughput screening for protein kinase inhibitors.
abstract: The pivotal role of kinases in signal transduction and cellular regulation has lent them considerable appeal as pharmacological targets across a broad spectrum of pathologies. Since the discovery that the v-Src oncogene encoded a protein kinase in 1978, kinases have remained a focus of research for pharmaceutical laboratories and academic groups alike. Many have sought to develop orally available low molecular weight synthetic kinase modulators (predominantly inhibitors) and thus capitalize on the links between aberrant regulation and disease. This interest in kinases as drug targets was fueled in recent years by the success of several kinase inhibitors in the clinic, primarily Gleevec for the treatment of chronic myelogenous leukemia and Iressa for the treatment of advanced non-small cell lung cancer. This review focuses on the development of small molecule drugs, most of them binding in or close to the ATP binding pocket. After some general considerations regarding the selection of a particular kinase for drug discovery, we will discuss the encouraging lessons learned from some of the kinase inhibitors currently in various stages of development. The majority of this review is dedicated to a detailed description and discussion of the various assay formats currently being employed for high throughput screening.
authors.affiliation: Amgen San Francisco, 1120 Veterans Blvd, South San Francisco, CA 94080, USA. hwesche@amgen.com
authors.forename: Holger
authors.initials: H
authors.lastname: Wesche
authors.forename: Shou-Hua
authors.initials: SH
authors.lastname: Xiao
authors.forename: Steve W
authors.initials: SW
authors.lastname: Young
mesh_terms: D000818:Animals; D001358:Avian Sarcoma Viruses / Q000378:metabolism; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D008175:Lung Neoplasms / Q000473:pathology; D008403:Mass Screening; D019151:Peptide Library; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases