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

Anne-Marie Egert-Schmidt; Jan Dreher; Ute Dunkel; Simone Kohfeld; Lutz Preu; Holger Weber; Jan E Ehlert; Bettina Mutschler; Frank Totzke; Christoph Schächtele; Michael H G Kubbutat; Knut Baumann; Conrad Kunick

doi:10.1021/jm901388c

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

J Med Chem. 2010 Mar 25;53(6):2433-42. doi: 10.1021/jm901388c.

Authors

Anne-Marie Egert-Schmidt¹, Jan Dreher, Ute Dunkel, Simone Kohfeld, Lutz Preu, Holger Weber, Jan E Ehlert, Bettina Mutschler, Frank Totzke, Christoph Schächtele, Michael H G Kubbutat, Knut Baumann, Conrad Kunick

Affiliation

¹ Technische Universitat Braunschweig, Institut für Pharmazeutische Chemie, Beethovenstrasse 55, 38106 Braunschweig, Germany.

PMID: 20170163
DOI: 10.1021/jm901388c

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzazepines / chemistry*
Benzazepines / pharmacology*
Binding Sites
Binding, Competitive
Cell Cycle Proteins / antagonists & inhibitors*
Cell Cycle Proteins / chemistry
Cell Cycle Proteins / metabolism
Cell Line
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Design
Endothelial Cells / cytology
Endothelial Cells / drug effects
Endothelial Cells / metabolism
Humans
Inhibitory Concentration 50
Models, Molecular
Molecular Structure
Phosphorylation / drug effects
Polo-Like Kinase 1
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / metabolism
Protein Structure, Tertiary
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins / chemistry
Proto-Oncogene Proteins / metabolism
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / chemistry
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Benzazepines
Cell Cycle Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyrimidines
Vascular Endothelial Growth Factor Receptor-2
Protein Serine-Threonine Kinases