title: Identification of 2-anilino-9-methoxy-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones as dual PLK1/VEGF-R2 kinase inhibitor chemotypes by structure-based lead generation.
abstract: To develop multikinase inhibitors with dual PLK1/VEGF-R2 inhibitory activity, the d-annulated 1-benzazepin-2-one scaffold present in the paullone family of kinase inhibitors was investigated as a general structure template suitable for anchoring annulated heterocycles at the hinge region of the ATP binding site. For this purpose, the indole substructure of the paullones was replaced by other nitrogen containing heteroaromatics. The designed scaffolds were synthesized and tested on the indicated kinases. The 2-anilino-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones were found to be VEGF-R2 inhibitors with selectivity against the insulin receptor kinase. The attachment of a methoxy group to the 9-position of the scaffold led to additional PLK1 inhibitory activity, which was explained by an alternative binding mode of the 9-methoxy derivatives. Selected members of the compound class inhibited the VEGF-R2 autophosphorylation in human umbilical vein endothelial cells, the sprouting of human umbilical vein endothelial cell speroids, and the proliferation of diverse cancer cell lines.
authors.affiliation: Technische Universitat Braunschweig, Institut für Pharmazeutische Chemie, Beethovenstrasse 55, 38106 Braunschweig, Germany.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Egert-Schmidt
authors.forename: Jan
authors.initials: J
authors.lastname: Dreher
authors.forename: Ute
authors.initials: U
authors.lastname: Dunkel
authors.forename: Simone
authors.initials: S
authors.lastname: Kohfeld
authors.forename: Lutz
authors.initials: L
authors.lastname: Preu
authors.forename: Holger
authors.initials: H
authors.lastname: Weber
authors.forename: Jan E
authors.initials: JE
authors.lastname: Ehlert
authors.forename: Bettina
authors.initials: B
authors.lastname: Mutschler
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.forename: Michael H G
authors.initials: MH
authors.lastname: Kubbutat
authors.forename: Knut
authors.initials: K
authors.lastname: Baumann
authors.forename: Conrad
authors.initials: C
authors.lastname: Kunick
mesh_terms: D001552:Benzazepines / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D001552:Benzazepines; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D040301:Vascular Endothelial Growth Factor Receptor-2; D000097869:Polo-Like Kinase 1