title: Structural insights into the conformational selectivity of STI-571 and related kinase inhibitors.
abstract: STI-571 (Gleevec) is a highly successful cancer drug due to its activity as an inhibitor of the Abelson cytoplasmic tyrosine kinase (Abl), which is constitutively active in a majority of patients with chronic myelogenous leukemia. STI-571 also inhibits two type III receptor tyrosine kinases, c-Kit and platelet-derived growth factor receptor, and functions by targeting inactive conformations of these kinases. This review focuses on recent developments in X-ray co-crystal structure analyses of STI-571 bound to Abl and the c-Kit receptor tyrosine kinase domain, and also three other relevant kinase inhibitor co-crystal structures. The similar structural features of these inactive kinases suggest they will be useful for the successful drug discovery and development of specific and targeted gene-based cancer drugs.
authors.affiliation: Syrrx Inc, La Jolla, CA 92121, USA. clifford.mol@syrrx.com
authors.forename: Clifford D
authors.initials: CD
authors.lastname: Mol
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: David J
authors.initials: DJ
authors.lastname: Hosfield
mesh_terms: D001549:Benzamides; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D000068877:Imatinib Mesylate; D008968:Molecular Conformation; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate