Abstract
Vascular endothelial growth factor receptor 2 (VEGFR-2) binds to VEGFR-A, VEGFR-C and VEGFR-D and participates in the formation of tumor blood vessels, mediates the proliferation of endothelial cells, enhances microvascular permeability, and blocks apoptosis. Blocking or downregulating the signal transduction of VEGFR is the main way to discover new drugs for many human angiogenesis-dependent malignancies. Mesenchymal epithelial transfer factor tyrosine kinase (c-Met) is a high affinity receptor for hepatocyte growth factor (HGF). Abnormal c-Met signaling plays an important role in the formation, invasion and metastasis of human tumors. Therefore, the HGF/c-Met signaling pathway has become a significant target for cancer treatment. Related studies have shown that the conduction of the VEGFR and c-Met signaling pathways has a synergistic effect in inducing angiogenesis and inhibiting tumor growth. In recent years, multi-target small molecule inhibitors have become a research hotspot, among which the research of VEGFR and c-Met dual-target small molecule inhibitors has become more and more extensive. In this review, we comprehensively summarize the chemical structures and biological characteristics of novel VEGFR/c-Met dual-target small-molecule inhibitors in the past five years.
Highlights
The occurrence of tumor is a multi-stage and complex process which seriously endangers human life and health [1]
The pyridine nucleus in receptor tyrosine kinase inhibitors can extend into the ATP binding pocket of Vascular endothelial growth factor receptor 2 (VEGFR-2) and c-Met receptors, and the nitrogen atom of the pyridine ring can interact with the amino acid residues in the hinge region
The results indicated that compound 1 was a dual inhibitor of VEGFR-2 and c-Met that holds promising potential
Summary
The occurrence of tumor is a multi-stage and complex process which seriously endangers human life and health [1]. Most of the compounds have entered into clinical trials to further evaluate their pharmacodynamic (PD) and pharmacokinetic (PK) properties, in order to explore their mechanism of action and evaluate their efficacy in vivo, side effects and drug resistance These compounds exhibited slight inhibitory effects against VEGFR and c-Met kinases, so their active skeletons are worthy of further study and may have a positive effect on the development of small anticancer inhibitors of dual-target VEGFR/c-Met kinase. The pharmacophores of VEGFR inhibitors and the pharmacophores of c-Met inhibitors are combined to form new dual-target VEGFR/c-Met inhibitors through the principles of skeleton and bioelectronic exclusion principle They contain the main structural features of two kinase drugs, which bind to the protein sequence of VEGFR and c-Met kinases or the binding site of ligands respectively, blocking the signaling and bypassing pathways of VEGFR and c-Met [41,56,57]. According to the structure of the parent cores, 11 derivatives are summarized, such as pyridines, quinolones, pyrrolopyridines, benzimidazoles and thienopyrimidines
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