VEGFR-2 inhibitor, also known as kinase insert domain receptor(KDR) inhibitor, are tyrosine kinase receptor inhibitors that reduce angiogenesis or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple signaling pathways involved in tumor, including proliferation, metastasis and angiogenesis.
VEGFR
The VEGF receptor family contains three members, which are all receptor tyrosine kinases (VEGFR-1, VEGFR-2 and VEGFR-3). VEGFR-1, or FLT-1 (fms-like tyrosine kinase), are important for hematopoietic stem cell development, VEGFR-2 (KDRor FLK-1 (fetal liver kinase)) are vital to vascular endothelial cell development and VEGFR-3 (FLT-4) for lymphatic endothelial cell development. Binding of VEGF to the VEGFR induces a conformational change in the receptor producing a signaling pathway.
VEGFR-2
VEGFR-2 is a 210-230 kDa glycoprotein expressed in vascular endothelial cells and in hematopoietic stem cells and binds VEGF-A. VEGFR-2 is closely related to VEGFR-1 for they have common and specific ligands but VEGFR-2 is a highly active kinase while VEGFR1 is an impaired receptor tyrosine kinase. This receptor is a regulator in responses in the endothelial cells of VEGF. These regulations include permeability, proliferation, invasion and migration. The signaling pathways, Y1175 and Y1214, are the main autophosphorylation sites of the human VEGFR-2 followed by VEGF binding. Autophosphorylated VEGFR-2 is required for activation of several downstream pathways, which are hyperactivated in some tumors. These signaling pathways are important in tumor angiogenesis, which stimulates tumor growth by supplying the tumor with oxygen and nutrients. VEGFR-2 is overexpressed in several cancers, for example ovarian, thyroid, melanoma and medulloblastoma.
Structure
VEGFR-2 are a part of the VEGF family. The other receptors in the family are VEGFR-1 and VEGFR-3. These receptors are a type of transmembrane kinase receptors and have similar structure. They have an extracellular part that is made up of an N-terminus signal and a 7 immunoglobulin-like domain. The intracellular part of the receptor consists of a juxtamembrane (the tyrosine kinase domain), which is divided to proximal and distal kinase domains and a C-terminus tail.
Medical Uses
Sorafenib is used as an oral drug which inhibits angiogenesis and tumor cell growth in VEGFR-2 and VEGFR-3 (inhibits the phosphorylation), PDGFRβ (platelet-derived growth factor receptor), RAF kinase, FLT3 (Fms-like tyrosine kinase-3) and KIT (stem cell factor receptor). Sorafenib is used in the treatment of advanced renal cell carcinoma. As of October 2018, it is in phase III of clinical trials for hepatocellular carcinoma, metastatic melanoma and non-small cell lung cancer (NSCLC). Sunitinib is an oral drug that inhibits the phosphorylation of all the VEGF receptors, PDGFR-ß, KIT FLT3, CSF1R and GDNF. Sunitinib is used in the treatment of advanced renal cell carcinoma and gastrointestinal stromal tumors. Bevacizumab is a humanized monoclonal antibody, which binds selectively to VEGF. It is used as an injection therapy, often in combination with other drugs. It is used in combination with 5-fluorouracil as a first-line treatment of metastatic carcinoma in the colon or rectum. In advanced non-small cell lung cancer bevacizumab (Avastin) is used as a first-line treatment in combination with paclitaxel and carboplatin. It can also be used in the treatment for breast cancer and kidney cancer.
Lenvatinib and vandetanib are used for the treatment of progressive and locally advanced differentiated thyroid cancer (DTC). Pazopanib and axitinib are used orally for the treatment of advanced renal cell carcinoma. Cabozantinib has the same indication but it is only used on patients who have already received an anti-angiogenic therapy. Regorafenib is administered orally for the treatment of colorectal cancer, gastrointestinal stromal cancer and hepatocellular carcinoma. Nintedanib is used for the treatment of idiopathic pulmonary fibrosis. Tests for liver function have to be made to modify doses before the therapy can start. Apatinib is used for the treatment of advanced gastric cancer. It is often diagnosed in late stages because there are no early signs or symptoms.