7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a 'Cut and Glue' Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors
| Autor: | Conrad Kunick, Frank Totzke, Michael H.G. Kubbutat, Stefan Knapp, Mehmet Karatas, Bianca Berger, Apirat Chaikuad |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Vascular Endothelial Growth Factor A
Pharmaceutical Science Benzazepinone X-ray structure analysis Analytical Chemistry 0302 clinical medicine Aurora kinase Aurora Kinase Drug Discovery Veröffentlichung der TU Braunschweig Sulfamide Aurora Kinase A chemistry.chemical_classification 0303 health sciences anilinopyrimidine protein kinase inhibitor Kinase Protein kinase inhibitor Ligand (biochemistry) 3. Good health Biochemistry ddc:54 Chemistry (miscellaneous) 030220 oncology & carcinogenesis Molecular docking ddc:540 Molecular Medicine Publikationsfonds der TU Braunschweig medicine.drug_class Anilinopyrimidine Aurora A kinase Antineoplastic Agents benzazepinone PLK1 Article lcsh:QD241-441 Structure-Activity Relationship 03 medical and health sciences lcsh:Organic chemistry Cell Line Tumor medicine Humans ddc:610 Physical and Theoretical Chemistry Protein kinase A Protein Kinase Inhibitors ddc:5 Cell Proliferation 030304 developmental biology Organic Chemistry molecular docking Benzazepines X-ray Structure Analysis sulfamide Enzyme chemistry |
| Zdroj: | Molecules Molecules 2021, 26(6), 1611; https://doi.org/10.3390/molecules26061611--Molecules annual : CD-ROM and print archive edition of Molecules, journal of synthetic organic and natural product chemistry--http://www.bibliothek.uni-regensburg.de/ezeit/?2008644--http://www.mdpi.com/journal/molecules--https://www.ncbi.nlm.nih.gov/pmc/journals/3416/--1420-3049--1420-3049 Volume 26 Issue 6 Molecules, Vol 26, Iss 1611, p 1611 (2021) |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules26061611 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|