title: The background, discovery and clinical development of BCR-ABL inhibitors.
abstract: The story of the inhibition of BCR-ABL as a treatment for chronic myelogenous leukaemia serves to illustrate key aspects of the kinase drug discovery and development process. Firstly, elucidation of the disease mechanism enabled identification of the molecular target(s) which catalysed pharmaceutical research and resulted in Gleevec(®) (Novartis) as the first FDA approved BCR-ABL inhibitor. However, clinical success was soon tempered by the emergence of drug resistance through various mechanisms. Using rational drug design, several hypotheses were devised to overcome resistance issues leading to the development of second generation inhibitors, providing clinicians and patients with greater therapeutic choice.
authors.affiliation: Department of Chemistry, University of York, Heslington, York YO10 5DD, United Kingdom; Cyclofluidic Limited, BioPark, Welwyn Garden City AL7 3AX, United Kingdom.
authors.forename: Gemma K
authors.initials: GK
authors.lastname: Lambert
authors.forename: Anne-Kathrin
authors.initials: AK
authors.lastname: Duhme-Klair
authors.forename: Trevor
authors.initials: T
authors.lastname: Morgan
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Ramjee
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl