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

Abstract

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.

Citrus Flavones: An Update on Sources, Biological Functions, and Health Promoting Properties

“…Another important protein, whose function can be regulated by chrysoeriol, is BCRP; in fact, the flavone is able to decrease drastically its efflux activity, reducing multidrug resistance typical of cancer cells [148]. Docking experiments and enzymatic assays have demonstrated that chrysoeriol is able also to bind and inhibit two kinases, VEGFR2 (vascular endothelial growth factor 2) and c-Met, both important for tumor progression and resistance to drugs [149]. 8-chrysoeriol, a derivate of chrysoeriol, can promote apoptosis by binding to the BH3 domain of Bcl2 antiapoptotic proteins, that are highly expressed in cancer cells, blocking their activity and inducing cells death [150].…”

Recent progress on vascular endothelial growth factor receptor inhibitors with dual targeting capabilities for tumor therapy

“…Structurally, the catalytic domain of VEGFR2, as a bi-lobed structure with a small N-lobe and a large C-lobe, plays a key role in the inhibitory potency of these inhibitors. Specifically, the active site of VEGFR2 consists of the following subregions: hydrophobic region I (encapsulated by the residues Leu840, Phe918 and Gly922), hydrophobic region II (encapsulated by the residues Leu889, Ile892, Val898 and Ile1044) and one linker region (encapsulated by the residues Ala866, Val914, Leu1035 and Cys1045) [45]. As shown in Fig.…”

Acacetin and Chrysoeriol: A Short Review of the Chemistry, Plant Sources, Bioactivities and Structure-Activity Relationships of these Methylated Flavones

“…A recent study on CSE and its analogues showed that they inhibited both mesenchymal-epithelial transition factor (c-Met) and vascular endothelial growth factor receptor 2 (VEGFR2) that are involved in tumorigenesis of certain types of cancer. 78 To address cancer drug resistance, further SAR analyzes are needed to guide structural optimizations.…”