7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors
Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic stru...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2021-03-01
|
Series: | Molecules |
Subjects: | |
Online Access: | https://www.mdpi.com/1420-3049/26/6/1611 |
id |
doaj-51761ca01db94910aaa8296ca059fde7 |
---|---|
record_format |
Article |
spelling |
doaj-51761ca01db94910aaa8296ca059fde72021-03-15T00:03:04ZengMDPI AGMolecules1420-30492021-03-01261611161110.3390/molecules260616117-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase InhibitorsMehmet Karatas0Apirat Chaikuad1Bianca Berger2Michael H. G. Kubbutat3Frank Totzke4Stefan Knapp5Conrad Kunick6Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, GermanyStructural Genomics Consortium, BMLS, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, GermanyInstitut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, GermanyReaction Biology Europe GmbH, 79108 Freiburg, GermanyReaction Biology Europe GmbH, 79108 Freiburg, GermanyStructural Genomics Consortium, BMLS, Max-von-Laue-Straße 15, 60438 Frankfurt am Main, GermanyInstitut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, GermanyAlthough overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines.https://www.mdpi.com/1420-3049/26/6/1611anilinopyrimidineAurora kinasebenzazepinonemolecular dockingprotein kinase inhibitorsulfamide |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mehmet Karatas Apirat Chaikuad Bianca Berger Michael H. G. Kubbutat Frank Totzke Stefan Knapp Conrad Kunick |
spellingShingle |
Mehmet Karatas Apirat Chaikuad Bianca Berger Michael H. G. Kubbutat Frank Totzke Stefan Knapp Conrad Kunick 7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors Molecules anilinopyrimidine Aurora kinase benzazepinone molecular docking protein kinase inhibitor sulfamide |
author_facet |
Mehmet Karatas Apirat Chaikuad Bianca Berger Michael H. G. Kubbutat Frank Totzke Stefan Knapp Conrad Kunick |
author_sort |
Mehmet Karatas |
title |
7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors |
title_short |
7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors |
title_full |
7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors |
title_fullStr |
7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors |
title_full_unstemmed |
7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors |
title_sort |
7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones designed by a “cut and glue” strategy are dual aurora a/vegf-r kinase inhibitors |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2021-03-01 |
description |
Although overexpression and hyperactivity of protein kinases are causative for a wide range of human cancers, protein kinase inhibitors currently approved as cancer drugs address only a limited number of these enzymes. To identify new chemotypes addressing alternative protein kinases, the basic structure of a known PLK1/VEGF-R2 inhibitor class was formally dissected and reassembled. The resulting 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones were synthesized and proved to be dual inhibitors of Aurora A kinase and VEGF receptor kinases. Crystal structures of two representatives of the new chemotype in complex with Aurora A showed the ligand orientation in the ATP binding pocket and provided the basis for rational structural modifications. Congeners with attached sulfamide substituents retained Aurora A inhibitory activity. In vitro screening of two members of the new kinase inhibitor family against the cancer cell line panel of the National Cancer Institute (NCI) showed antiproliferative activity in the single-digit micromolar concentration range in the majority of the cell lines. |
topic |
anilinopyrimidine Aurora kinase benzazepinone molecular docking protein kinase inhibitor sulfamide |
url |
https://www.mdpi.com/1420-3049/26/6/1611 |
work_keys_str_mv |
AT mehmetkaratas 72anilinopyrimidin4yl1benzazepin2onesdesignedbyacutandgluestrategyaredualauroraavegfrkinaseinhibitors AT apiratchaikuad 72anilinopyrimidin4yl1benzazepin2onesdesignedbyacutandgluestrategyaredualauroraavegfrkinaseinhibitors AT biancaberger 72anilinopyrimidin4yl1benzazepin2onesdesignedbyacutandgluestrategyaredualauroraavegfrkinaseinhibitors AT michaelhgkubbutat 72anilinopyrimidin4yl1benzazepin2onesdesignedbyacutandgluestrategyaredualauroraavegfrkinaseinhibitors AT franktotzke 72anilinopyrimidin4yl1benzazepin2onesdesignedbyacutandgluestrategyaredualauroraavegfrkinaseinhibitors AT stefanknapp 72anilinopyrimidin4yl1benzazepin2onesdesignedbyacutandgluestrategyaredualauroraavegfrkinaseinhibitors AT conradkunick 72anilinopyrimidin4yl1benzazepin2onesdesignedbyacutandgluestrategyaredualauroraavegfrkinaseinhibitors |
_version_ |
1724221179897577472 |