7AYI

Crystal structure of Aurora A in complex with 7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-one derivative (compound 2a)

Summary for 7AYI

• Entry DOI: 10.2210/pdb7ayi/pdb
• Descriptor: Aurora kinase A, 7-(2-phenylazanylpyrimidin-4-yl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (2 entities in total)
• Functional Keywords: kinase, kinase inhibitor, aurora kinase, stk6, structural genomics, structural genomics consortium, sgc, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 33279.16

Authors

Chaikuad, A.,Karatas, M.,Kunick, C.,Knapp, S.,Structural Genomics Consortium (SGC) (deposition date: 2020-11-12, release date: 2021-01-13, Last modification date: 2024-01-31)

Primary citation

Karatas, M.,Chaikuad, A.,Berger, B.,Kubbutat, M.H.G.,Totzke, F.,Knapp, S.,Kunick, C.
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, 26:-, 2021

PubMed Abstract: 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.

PubMed: 33799460
DOI: 10.3390/molecules26061611

Experimental method

X-RAY DIFFRACTION (2.86 Å)