10.1021/jm901388c
The study presents the identification and development of dual PLK1/VEGF-R2 kinase inhibitors based on the 2-anilino-9-methoxy-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-ones chemotype. Researchers explored the potential of the d-annulated 1-benzazepin-2-one scaffold, found in the paullone family of kinase inhibitors, as a template for designing inhibitors that could target both PLK1 and VEGF-R2. They synthesized and tested various scaffolds, finding that those with a 9-methoxy group on the scaffold showed additional PLK1 inhibitory activity beyond their VEGFR2 inhibition. The study includes detailed synthetic methods, biological evaluations, and molecular docking studies to understand the binding modes of the compounds. The most promising compounds were found to inhibit VEGF-R2 autophosphorylation in human umbilical vein endothelial cells, sprouting of endothelial cell speroids, and proliferation of various cancer cell lines, offering a potential therapeutic approach for cancer treatment by targeting both cell division and tumor vascularization.
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