Structure activity relationships of chrysoeriol and analogs as dual c ‐ Met and VEGFR 2 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. Introduction Vascular endothelial growth factor receptor 2 (VEGFR2) is a tyrosine kinase receptor, mainly expressed in endothelial cells. In several types of solid tumor, VEGFR2 is critical in tumor angiogenesis, allowing tumor cells to receive sufficient nutrients and oxygen to grow. The inhibition of VEGFR2 has been shown to cause hypoxia and necrosis of solid tumors (1). Therefore, VEGFR2 has become a promising target for tumor treatment (2). Unfortunately, patients can develop resistance to VEGFR2 inhibitors and this resistance correlates with poor prognosis. It is suggested that the mechanism underlying this resistance involves c-Met (1). The inhibition of VEGFR2 causes tumor hypoxia and activates the hypoxia inducible factor 1α regulatory pathway, leading to enhanced expression of c-Met, which can promote tumor metastasis and establish a vicious circle of hypoxia and malignant metastasis (1). Therefore, the inhibition of c-Met may have the potential to overcome the resistance to VEGFR2 inhibition. Dual c-Met and VEGFR2 kinase inhibitors have attracted considerable attention in studies (3-5). c-Met is a tyrosine kinase receptor for hepatocyte growth factor and has become an important target for the treatment of several types of solid tumor (6). The activation of c-Met is associated with several physiological processes, including cell proliferation, survival, morphogenesis and angiogenesis (7). Studies have shown the upregulation of c-Met in various type of cancer, which correlates with a poor prognosis. Therefore, c-Met inhibitors have been used to treat patients and have produced beneficial results (8). Previously, it was found that c-Met and VEGFR2 act synergistically in several types of cancer, and they share partial signal pathways (9-11). Therefore, dual c-Met and VEGFR2 kinase inhibitors have the potential to improve therapeutic outcomes. To date, several dual c-Met and VEGFR2 inhibitors are available for clinical use (10), however, their selectivity is low and they cause several side effects, which are due to their relatively simple structures of either quinolones/quinazolines or pyridine. Therefore, the development of a novel structure Structure activity relationships of chrysoeriol and analogs as dual c‐Met and VEGFR2 tyrosine kinase inhibitors SHUANG LAI1*, JUN-NING CHEN2*, HAN-WEI HUANG3*, XIANG-YU ZHANG2, HAI-LUN JIANG2, WEI LI4, PENG-LIANG WANG3, JIAN WANG2 and FU-NAN LIU3 1Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001; 2Key Laboratory of Structure-Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016; 3Department of Surgical Oncology and General Surgery, First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001; 4Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, Shenyang, Liaoning 110042, P.R. China Received February 6, 2018; Accepted June 25, 2018 DOI: 10.3892/or.2018. 6542 Correspondence to: Dr Fu-Nan Liu, Department of Surgical Oncology and General Surgery, First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Shenyang, Liaoning 110001, P.R. China E-mail: lfn540@126.com *Contributed equally