TY  - JOUR
A1  - Karatas, Mehmet
A1  - Chaikuad, Apirat
A1  - Berger, Bianca
A1  - Kubbutat, Michael H. G.
A1  - Totzke, Frank
A1  - Knapp, Stefan
A1  - Kunick, Conrad
T1  - 7-(2-anilinopyrimidin-4-yl)-1-benzazepin-2-ones designed by a "cut and glue" strategy are dual aurora A/VEGF-R kinase inhibitors
T2  - Molecules
N2  - 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.
KW  - anilinopyrimidine
KW  - Aurora kinase
KW  - benzazepinone
KW  - molecular docking
KW  - protein kinase inhibitor
KW  - sulfamide
KW  - X-ray structure analysis
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62141
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-621418
SN  - 1420-3049
N1  - This research was funded by the European Commission, Contract No LSHB-CT-2004-503467 (to B.B. and C.K.). We acknowledge support by the German Research Foundation and the Open Access Publication Funds of Technische Universität Braunschweig. S.K. and A.C. acknowledge support by the SGC, a registered charity (no: 1097737) that receives funds from; AbbVie, Bayer AG, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genentech, Genome Canada through Ontario Genomics Institute [OGI-196], EU/EFPIA/OICR/McGill/KTH/Diamond, Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant 875510), Janssen, Merck KGaA (aka EMD in Canada and US), Merck & Co (aka MSD outside Canada and US), Pfizer, São Paulo Research Foundation-FAPESP, Takeda and Wellcome. S.K. is grateful for support from the German translational Cancer Network DKTK and the Frankfurt Cancer Institute (FCI).
VL  - 26
IS  - 6, art. 1611
SP  - 1
EP  - 26
PB  - MDPI
CY  - Basel
ER  -