title: Synthesis of an aryloxy oxo pyrimidinone library that displays ALK-selective inhibition.
abstract: We report the synthesis of a pyrimidinone library that targets anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase. This library was generated in three steps from a versatile commercially available starting material. Some compounds within this library showed single digit micromolar inhibition of ALK in vitro, while showing minimal inhibition of other homologous insulin receptor family kinases including the human insulin receptor kinase (IRK), at the highest concentrations investigated. We also present initial ALK structure-activity relationships for this library.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, United States.
authors.forename: P Jake
authors.initials: PJ
authors.lastname: Slavish
authors.forename: Jeanine E
authors.initials: JE
authors.lastname: Price
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Cui
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Morris
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D015703:Antigens, CD / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D015703:Antigens, CD; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C435941:INSR protein, human; D020794:Receptor Protein-Tyrosine Kinases; D011972:Receptor, Insulin