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The VEGF receptor family contains three members, which are all receptor tyrosine kinases (VEGFR-1, VEGFR-2 and VEGFR-3).[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)[4] for lymphatic endothelial cell development.[2] Binding of VEGF to the VEGFR induces a conformational change in the receptor producing a signaling pathway.[3]
VEGF-A.[2][4]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.[2] These signaling pathways are important in tumor angiogenesis, which stimulates tumor growth by supplying the tumor with oxygen and nutrients.[3] VEGFR-2 is overexpressed in several cancers, for example ovarian, thyroid, melanoma and medulloblastoma. [2]
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
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.[2]
Bevacizumab is a humanized monoclonal antibody, which binds selectively to VEGF receptor. 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.[5]300px|thumb|right|Lenvatinib binding to VEGFR-2Lenvatinib and vandetanib are used for the treatment of progressive and locally advanced differentiated thyroid cancer (DTC).[6][7]Pazopanib and axitinib are used orally for the treatment of advanced renal cell carcinoma.[8][9]Cabozantinib has the same indication but it is only used on patients who have already received an anti-angiogenic therapy.[10]Regorafenib is administered orally for the treatment of colorectal cancer, gastrointestinal stromal cancer and hepatocellular carcinoma.[11]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.[11]Apatinib is used for the treatment of advanced gastric cancer. It is often diagnosed in lage stages because there are no early signs or symptoms.[12]
Mechanism of action
Binding to VEGF receptor induces dimerization, which modifies the conformation in the intracellular domain. These modification lead to the exposure of the ATP-binding site, which causes ATP binding on the receptor and also transphosphorylation on specific tyrosine residues. Tyrosine phosphorylation on the receptor is regulated by internalization, degradation and by dephosphorylation through different protein tyrosine phosphatases. This can then lead to the initial receptor signal transduction cascade, which activates several downstream enzymatic pathways.[2]
The signaling inhibition of VEGFR is through tumor vessel and not the tumor cells. Reduction of VEGF expression reduces blood flow to tumor and stops tumor angiogenesis.[4]
Adverse Effects
VEGF inhibitors in the treatment of cancer often cause
adverse effects. Treatment with VEGF inhibitors suppresses cellular signalling pathways that are important in microvasculature regulation and maintenance. The effects on normal organs can then lead to vascular disturbances and regression of blood vessels. Adverse effect is an undesired effect happening as a result of an intervention such as medication. Adverse effects are graded on a scale from 0-5 where grade 0 stands for no adverse effects, grade 1 stands for mild, grade 2 stands for moderate, grade 3 stands for severe and undesirable, grade 4 stands for life-threatening or disabling and grade 5 is fatal.[5]
FDA has approved three drugs, bevacizumab, sunitinib and sorafenib that were developed for antiangiogenic actions and are used in the treatment of patients with specific cancer types. All of these drugs have the mechanism of inhibiting VEGF signalling by blocking either the function of the VEGF ligand or VEGF receptor.[5]
Bevacizumab is a function-blocking monoclonal antibody that binds selectively to VEGF. Generally bevacizumab is well tolerated and safe but can have adverse effects which can be intensified by chemotherapeutic agents used at the same time. For bevacizumab the most common adverse effects are
Sunitinib is a small molecule inhibitor which inhibits phosphorylation of VEGF receptor among other receptors. Sunitinib is mostly well tolerated. Common adverse effects which have an incidence rate of 20% are fatigue,
Sorafenib is a small molecule inhibitor of many tyrosine kinase receptors such as VEGFR-2. Side effects connected with sorafenib are in most cases mild to moderate such as rash, hand-foot skin reaction, diarrhea, dermatitis which occur in about 33-38% patients using sorafenib. Other side effects are mild hypertension, leukopenia and bleeding. Uncommon side effects are cardiac ischaemia or infarction, gastrointestinal perforation, life-threatening haemorrhage and reversible posterior leukoencephalopathy syndrome.[5]
Hypertension is one of the most common side effects regarding inhibition of VEGF signalling. VEGF increases synthesis of NO through upregulation of endothelial NO synthase and therefore inhibition of VEGF diminishes NO synthesis. Decrease in NO causes
peripheral resistance and increases blood pressure. Hypertension caused by VEGF inhibition can usually be treated with oral antihypertensive agents.[5]
glomerular capillary endothelial cells and is activated by VEGF. Therefore the inhibition of VEGF causes proteinuria. Proteinuria is in most cases asymptomatic and usually decreases when treatment ends.[5]
Impaired wound healing can be an adverse effects of VEGF inhibition as angiogenesis is an important step in wound healing and agents that impair blood vessel growth can therefore be expected to have an impact on wound healing.[5]
phospholipids could be exposed on the plasma membrane or the underlying matrix which could lead to either thrombosis or haemorrhage. Since VEGF increases production of NO and prostacyclin the inhibition of VEGF leads to decrease in both chemicals which contributes to thromboembolic events.[5]
Reversible posterior leukoencephalopathy is often attributed to hypertensive encephalopathy as well as endothelial dysfunction which can cause the
cerebral oedema and vasospasm. Inhibition of VEGF is implicated as a factor in the pathophysiology of the disease but has not yet been replicated after VEGF inhibition in preclinical models. [5]
pituitary, adrenal cortex and pancreatic isle have also regressed as an effect of VEGF inhibition. The thyroid-hypothalamic feedback loop has also been impaired due to VEGF inhibition and elevation of TSH blood reported.[5]
Sunitinib is metabolized in the liver by CYP3A4. It interacts with inducers and inhibitors of CYP3A4 leading to a decrease or increase in the plasma concentration of particular drugs metabolized by the same way. It will not change the amount of drug metabolized by the enzyme, because it does not inhibit or induce the enzyme directly. Sunitinib is a substrate of
ABCG2 transporters. It acts as a inhibitor of ABCG2, more than the inhibition of P-glycoprotein. Drugs that are substrates of these carriers will be pharmacokinetically modified.[13]
Sorafenib increases the plasma concentration of paclitaxel in combination with carboplatin, but has no effect on carboplatin. It also increases the AUC (area under the curve) of docetaxel, doxorubicin and irinotecan but decreases the AUC of fluorouracil and neomycin, so it is cautionary when administering sorafenib with these drugs because the plasma concentration can be altered. Sorafenib is metabolized by CYP3A4 and UGT1A9. This means that every drug metabolized by these pathways have to be carefully administered. Sorafenib inhibits the UGT1A9 and UGT1A1, where the plasma concentration of other drugs could increase. The same goes for the CYP2B6 and CYP2C8 pathways, sorafenib inhibits them. Inducers of CYP3A4 can decrease the plasma concentration of sorafenib, combination with rifampicin. CYP3A4 inhibitors are unlikely to have an effect on sorafenib. Sorafenib is a competitive inhibitor of CYP2C19, CYP2D6 and CYP3A4. It inhibits P-glycoprotein, therefore it can increase the plasma concentration of drugs which are P-glycoprotein substrates.[14]
Pazopanib is metabolized in the liver by CYP3A4 enzyme. Strong CYP3A4 inhibitors, other than pazopanib, can increase the plasma concentration of pazopanib and the opposite with CYP3A4 inducers. Grapefruit juice is an CYP3A4 inhibitor and should be avoided when taking pazopanib. It is a weak inhibitor of other liver enzymes, CYP2C8 and CYP2D6.[8]
Axitinib is metabolized by CYP3A4 and UGT1A1. Strong inhibitors of CYP3A4 will increase the plasma concentration of axitinib, weak inhibitors can have a less effect on the plasma concentration. Strong inducers of CYP3A4 will decrease the plasma concentration of axitinib and should be avoided.[15]
Pipeline drugs
cytotoxic or antiproliferative effects on cells that do not express VEGF in concentrations lower than 10 μM. Specific inhibition of tumor-induced angiogenesis like the inhibition by Vatalanib can both prevent ongoing growth of tumors as the metastatic potential.[19]Cediranib is a multi VEGFR 1-3 inhibitor being tested as a maintenance treatment for patients with platinum sensitive relapsed ovarian cancer.[20][21] Cediranib stops blood flow to the site of the tumour and thereby inhibits the growth of the tumour.[20]
Structure-activity relationship (SAR)
Quinoline and quinazoline-derivatives
Lenvatinib, Vandetanib, Cabozantinib are drugs that belong to this group.[4]
Novel biphenyl tricyclic quinazoline compounds and aryloxy quinolone derivatives are multiple kinase inhibitors, which are less likely to lead to drug resistance than selective inhibitors. That means increased life expectancy.
4-quinazolinamine heterocyclic compounds and 2-chloro-4-anilino-quinazoline derivatives inhibit tumor vessel generation and restrain
Quinoxaline derivatives with a diaryl-amide or diaryl-urea substructure have B-Raf mutant kinase inhibition activity.
Some novel quinazoline derivatives inhibit Raf kinase selectively and have less effect on inhibition of VEGFR-2 and EGFR kinase.
A
hydrophobic effect with the hydrophobic pocket of VEGFR-2, especially the terminal phenyl group substituted by para-Cl.[4]
Quinolone-urea containing VEGFR inhibitors will bind to Asp1046 residue of the receptor via the carbonyl O, and interact with Glu885 residue via two NH groups.[4]
Urea derivatives
Urea derivatives on the market are Regorafenib and Sorafenib.
The urea derivatives block the VEGFR and/or one or more protein kinases and can therefore modulate, regulate and/or inhibit tyrosine kinase signal transduction.
Increased stability against degradation by liver enzymes can be acquired by adding a deuterium to heterocyclic compounds.
Novel urea compounds with pentafluoro-sulfane substitute on a phenyl group show better protein kinase inhibition in diseases like cancer when compared to aryl-urea compounds with either quinazoline or pyrimidine moieties.
N-substituted phenyl N’-substituted heterocyclic urea compounds give an IC50 between 15 nM and 1 μM for VEGFR-2.
Having a 1H-indole-1-carboxamide scaffold on aryl-urea compounds results in added VEGFR-2 potency and selectivity and gives an IC50 of 3nM against the receptor.[4]
Indolin derivatives
Indolin derivatives on the market are Sunitinib and Intedanib.[4]
Two Indol derivatives that targets the VEGF pathway, Semaxanib and Sunitinib have been developed, the former is potent but was inefficient in clinical trials and the latter has many side effects. There is need for new drug that has pharmacological effects like Semaxanib and Sunitinib but are less toxic. mPEG3-9-semaxanib is Semaxanib with additional water-soluble, non-peptidic oligomer attached to it via a spacer moiety. mPEG3-9-semaxanib derivatives are 10 times more VEGFR-2 active than Sunitinib. Compounds with sunitinib heterocyclic moiety but different amide side chains inhibit VEGFR-1 and VEGFR-2 and regulate disorders. Another compound with sunitinib heterocyclic moiety and pyrrole side chain are very good VEGFR-2 potency, with an IC50 of 65 nM. N-indol-1-amide compound is a possible anti-tumor drug in combination with other anticancer treatment and has IC50 value of 31 nM.[4]
There are many Indol derivatives with different side chains that target multiple kinases and are taking part in multiple pathways in tumor development.
Intedanib is a multiple tyrosine kinase inhibitor and is the first drug to treat idiopathic pulmonary fibrosis.[4] Indol derivatives with 1-NH of 2-indolinone motif that acts like an H-bond donor, and 2-carbonyl O that acts as an H-bond acceptor, bind with Glu915 and Cys917, respectively. These compounds have basic amine side chains or nitrogen heterocycles and provide ideal solubility and pharmacokinetics. These compounds are promising anti cancer and anti fibrosis drug and inhibit various protein tyrosine kinases. They have higher efficiency, lower toxicity, less side effects, favorable preparation technology and favorable physicochemical property. [4]
Pyridine derivatives
Pyridine derivatives on the market are Axitinib, Regorafenib and Apatinib.[4]
Pyridine derivatives with thiazolyamino-substituted heterocycle derivatives are kinase inhibitors. They show antiangiogenesis activity and
anti-proliferation in tumor cells. It is hypothesized that presence of sulfur atom in the heterocyclic ring enhances potency on inhibiting VEGFR-2. Compounds with thieno [3,2-b] pyridine urea moiety are inhibitory for VEGF receptor signaling and HGF receptor signaling. HGF and HGF receptors undermine the activity of VEGF inhibition.[4]
Pyridine derivatives with benzazepine have stronger selectivity and anti-tumor activity and less toxic side effects. They target many receptors like
c-Met, VEGFR2, EGFR and therefore show inhibitory activity on varieties of tumors. Compounds with no fluorine atom in the benzazepine inhibit multiple targets and have better in vitro enzyme inhibiting activity.[4]
3-chloro derivatives and 3-methoxy-N-methyl-2-pyridine carboxamide derivatives inhibit, modulate and regulate tyrosine kinase signal transduction. Diseases that are VEGFR2 related are treated with the above mentioned compounds in conjugation with other cancer therapies.
1-(5-tert-butyl-2-aryl-pyrazol-3-yl)-3-[2-fluoro-4-[(3-oxo-4H-pyrido[2,3-b] pyrazin-8-yl) oxy] phenyl] urea compounds are RAF inhibitors and treat disorders like cancer,
viral infections, fibrotic disorders, disorders associated with a mutated form of RAF.[4]
Pyrimidine derivatives
Pazopanib is a multi-targeted tyrosine kinase receptor inhibitor. The structure is formed by indazole, pyrimidine and a benzene ring.[22]
If the indazole ring is kept the same, replacing 5-amino-2-methylbenzenesulfonamide with other arylamine at position 2 of the pyrimidine, showed the inhibitory effect to VEGFR-2 and c-Kit. Compounds that showed this inhibitory effect that was synthesised a methyl group was in position R1. For R2, two groups can show this effect on the compound, an ether group and on the other a chloride group. When substituents are added on pazopanib with different electronic effects at the benzene ring the inhibition to the kinase changed.[22]
When looking at the steric effect on position R1 and R2 it has been shown that hydrogen in position R1 and trifluoro-ether in R2 had the most inhibitory effect on VEGFR-2, which can be the effect of the electronegative groups. There is a steric hindrance of the indazole heterocycle, which can play an important role with the interaction with the tyrosine kinase receptor inhibition.[22]