title: Tricyclic azepine derivatives: pyrimido[4,5-b]-1,4-benzoxazepines as a novel class of epidermal growth factor receptor kinase inhibitors.
abstract: A novel class of pyrimido[4,5-b]-1,4-benzoxazepines is described as inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase. Two compounds display potent EGFR inhibitory activity of less than 1 microM in cellular phosphorylation assays (IC(50) 0.47-0.69 microM) and are highly selective against a small kinase panel. Such compounds demonstrate anti-EGFR activity within a class that is different from any known EGFR inhibitor scaffolds. They also provide a basis for the design of kinase inhibitors with the desired selectivity profile.
authors.affiliation: Department of Chemistry, ImClone Systems, 180 Varick Street, New York, NY 10014, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Smith
authors.forename: Evgueni L
authors.initials: EL
authors.lastname: Piatnitski
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Xiaohu
authors.initials: X
authors.lastname: Ouyang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Chen
authors.forename: Sabina
authors.initials: S
authors.lastname: Burdzovic-Wizemann
authors.forename: Yongjiang
authors.initials: Y
authors.lastname: Xu
authors.forename: Weitao
authors.initials: W
authors.lastname: Pan
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Robin L
authors.initials: RL
authors.lastname: Rosler
authors.forename: Sheetal N
authors.initials: SN
authors.lastname: Patel
authors.forename: Hui-Hsien
authors.initials: HH
authors.lastname: Chiang
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Milligan
authors.forename: John
authors.initials: J
authors.lastname: Columbus
authors.forename: Wai C
authors.initials: WC
authors.lastname: Wong
authors.forename: Jacqueline F
authors.initials: JF
authors.lastname: Doody
authors.forename: Yaron R
authors.initials: YR
authors.lastname: Hadari
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D000255:Adenosine Triphosphate; D001381:Azepines; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases