Research Progress of Small Molecule VEGFR/c-Met Inhibitors as Anticancer Agents (2016–Present)

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.

Recent developments in anticancer kinase inhibitors based on the pyrazolo[3,4-d]pyrimidine scaffold

“…Tumours initiate the process of angiogenesis through VEGFs to provide them with nutrients, allowing them to grow. 134 Inhibition of these receptors has been used to starve tumour environments of nutrients and potentially limit their growth. Sorafenib ( 51 ) was the first VEGFR inhibitor approved by the FDA for use in renal cell carcinoma.…”

LncRNA UCA1 mediates Cetuximab resistance in Colorectal Cancer via the MiR-495 and HGF/c-MET Pathways

“…Here, siRNA-mediated c-MET downregulation or PHA-665752-mediated c-MET tyrosine kinase activity inhibition prevented HGF-dependent activation of the PI3K/AKT and MAPK pathways and resensitized cells to cetuximab-induced growth-inhibitory effects. Many c-MET-targeting therapeutics, including TKIs, mAbs, and molecular decoys, are currently undergoing clinical development [62][63][64][65]. The efficacy and safety of combined receptor tyrosine kinase (RTK) therapy should be evaluated in vivo to overcome EGFR TKI resistance in the future.…”

Design, Synthesis, and Biological Evaluation of [1,2,4]triazolo[4,3-a] Pyrazine Derivatives as Novel Dual c-Met/VEGFR-2 Inhibitors

“…Moreover, enormous small-molecule c-Met inhibitors have been reported and entered clinical studies ( Pasquini and Giaccone, 2018 ). These inhibitors can be classified into three types on the basis of the structural characters and the binding model to c-Met kinase: Class I, Class II, and the others ( Zhang et al, 2020c ). Class I c-Met inhibitors bind to ATP-binding sites to form a “U” shape, such as crizotinib (1), AMG337 (2) ( Boezio et al, 2016 ), PF-04217903 (3) ( Cui et al, 2012 ), and SGX-523 (4) ( Buchanan et al, 2009 ).…”