Structure activity relationships of chrysoeriol and analogs as dual c‑Met and VEGFR2 tyrosine kinase inhibitors

: Vascular endothelial growth factor receptor 2 (VEGFR2) and c‑Met are tyrosine kinases, which are involved in the tumorigenesis of various types of cancer. Previous studies have demonstrated that the elevated activation of c‑Met is associated with the drug resistance of VEGFR2 inhibitors. Therefore, dual c‑Met and VEGFR2 kinase inhibitors are expected to overcome VEGFR2 inhibitor resistance and subsequently lead to a superior therapeutic outcome to regular VEGFR2 inhibitors. In the present study, it was found that chrysoeriol, which can be extracted from several natural plants, was a potential dual c‑Met and VEGFR2 kinase inhibitor. The results of docking experiments revealed that chrysoeriol was able to efficiently bind in the active site cavity of c‑Met and VEGFR2. The results of enzymatic assays showed relatively high binding affinities of chrysoeriol to c‑Met (Kd=12 µM) and VEGFR2 (Kd=11 µM). The structure activity relationships (SARs) of chrysoeriol and its analogs were investigated using pharmacological and molecular docking experiments. To the best of our best knowledge, the present study is the first to report a natural product with both c‑Met and VEGFR2 inhibitory profiles, and provides insights into future dual c‑Met and VEGFR2 kinase inhibitor development.