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 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.

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Author:Mehmet Karatas, Apirat ChaikuadORCiD, Bianca Berger, Michael H. G. Kubbutat, Frank Totzke, Stefan KnappORCiD, Conrad Kunick
Parent Title (English):Molecules
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/03/14
Date of first Publication:2021/03/14
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/10/19
Tag:Aurora kinase; X-ray structure analysis; anilinopyrimidine; benzazepinone; molecular docking; protein kinase inhibitor; sulfamide
Issue:6, art. 1611
Page Number:26
First Page:1
Last Page:26
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).
Institutes:Biochemie, Chemie und Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0