VEGFR inhibitors

VEGFR inhibitors are a group of structurally distinct drugs, targeted tumor therapeutics that bind to one of the receptors of the growth factor VEGF (VEFG-R), thereby inhibiting angiogenesis. EGFR inhibitors are widely used for the treatment of metastatic renal cell carcinoma, gastrointestinal stromal tumors and hepatocellular carcinoma. Furthermore, for the indications: colon carcinoma, non-small cell lung carcinoma, pancreatic carcinoma, thyroid carcinoma, ovarian carcinoma, breast carcinoma, melanoma, medulloblastoma, glioblastoma as well as versch. Sarcomas etc.

VEGFR inhibitors have the same mode of action as VEGF inhibitors. They inhibit the signaling cascade induced by the VEGF receptor. In some cases, the terms are used synonymously in clinical usage. However, VEGF inhibitors bind to ligands of the receptor, to the signal molecule VEGF, whereas VEGFR inhibitors form a direct bond with the extracellular domain of the receptor, so that the ligand cannot dock.

Another group that inhibits the activity of VEGF-R are substances that inhibit the activity of the receptor by binding in close proximity to the ATP-binding site of the kinase, thus inhibiting the important step ATP binding.

The VEGF receptor family contains three subtypes, which are all receptor tyrosine kinases (VEGFR-1, VEGFR-2 and VEGFR-3):

• VEGFR-1 (Flt-1 = fms-like tyrosine kinase): VEGFR-1 is a regulator of endothelial cell responses such as migration and invasion. There is also a non membrane-bound, soluble form (sFlt1).
• VEGFR-2 (KDRor FLK-1 =fetal liver kinase): VEGFR-2 is a glycoprotein with 210-230 kDa which is expressed in vascular endothelial cells and in hematopoietic stem cells and binds VEGF-A. VEGF-2 is a highly active kinase and is responsible for almost all cellular responses to VEGF. Autophosphorylated VEGFR-2 controls angiogenesis and vasculogenesis in the human body. VEGFR-2 is closely related to VEGFR-1 because they share common specific ligands. VEGFR-2 is overexpressed in several tumour types, including ovarian and thyroid cancer, melanoma, medulloblastoma and glioblastoma (Musumeci F et al. 2012; Pham K et al. 2015).
• VEGFR-3 (Flt-4 = fms-like tyrosine kinase): regulates lymphangiogenesis in response to VEGF-C and VEGF-D. Unlike VEGFR-1 and VEGFR-2, VEGF-A is not an active ligand of VEGFR-3.

The binding of VEGF ligands to a VEGF receptor leads to a conformational change, dimerization of the receptor. This releases an ATP binding site , allowing ATP to bind to the intracellular domain of the receptor. This intracellular domain consists of the tyrosine kinase domain, which is divided into a proximal and a distal kinase domain and a C-terminal tail. Binding to the receptor triggers transphosphorylation of the intracellular tyrosine residues of the dimerized receptors. The activation of transcription factors influences proliferation, migration of endothelial cells and thus vasculogenesis.

VEGF inhibitors block the VEGF receptor so that the VEGF effect at the receptor is cancelled. The intracellular signalling cascade activated via the receptor is blocked. This results in an inhibition of angiogenesis. The latter is essential for the growth of tumours, but also for proliferative physiological or pathological vascular processes (e.g. wound healing, e.g. wet macular degeneration). The antineoplastic effect therefore does not affect the tumor cells themselves, but the vascular supply of the tumor parenchyma. If the blood supply of the tumour is no longer sufficient, a regression of the tumour parenchyma occurs (Madu CO et al. 2020).

Small molecule inhibitors of angiogenesis so-called "small molecules" are active in a variety of malignancies and fill a unique niche for cancer therapeutics (Ivy SP et al. 2009). These include the drugsatalanib, sunitinib, sorafenib, and vandetanib. Small molecules bind to the intracellular part of a receptor tyrosine kinase or a non-receptor tyrosine kinase (kinase domain) and block phyophorylation and activation by ATP. However, some of these chemicals block not only VEGF receptor tyrosine kinase but also serine threonine kinases (e.g. sunitinib), and are then called multi-kinase inhibitors. Aspects of radiosynthesis as well as the radiopharmacological oncological use of "small molecules" extend the additional armamentarium of this substance group (Kniess T 2012).

Others: Thalidomide and its derivatives lenalidomide and pomalidomide (approved for multiple myeloma therapy) have antineoplastic effects by inhibiting cell adhesion molecules, but also block angiogenesis by interference with interleukin-6 (Il-6) and by immunomodulation by controlling the cytotoxicity of NK and killer cells.

See below and the individual preparations

1. Harrison CA (2012) Deeper understanding of VEGFR inhibitors. Nat Rev Cancer 12: 735.
2. Ivy SP et al (2009) An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol. 6: 569-579.
3. Itatani Y et al (2018) Resistance to Anti-Angiogenic Therapy in Cancer-Alterations to Anti-VEGF Pathway. Int J Mol Sci 19:1232.
4. Kniess T (2012) Radiolabeled small molecule inhibitors of VEGFR - recent advances. Curr Pharm Des. 18:2867-2874.
5. Li G et al (2018) VEGFR-2 inhibitor Apatinib Hinders Endothelial Cells Progression Triggered by Irradiated Gastric Cancer Cells-derived Exosomes. J Cancer 9: 4049-4057.
6. Lugović-Mihić L et al. (2017) Drug-Induced Photosensitivity - a Continuing Diagnostic Challenge. Acta Clin Croat 56:277-283.
7. Madu CO et al (2020) Angiogenesis in Breast Cancer Progression, Diagnosis, and Treatment. J Cancer 11:4474-4494.
8. Modi YS et al (2015) Comparative safety and tolerability of anti-VEGF therapy in age-related macular degeneration. Drug Saf 38: 279-93
9. Musumeci F et al (2012) Vascular Endothelial Growth Factor (VEGF) Receptors: Drugs and new inhibitors. Journal of Medicinal Chemistry 55: 10797-10822.
10. Papadopoulos N et al (2012) Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 15:171-185.
11. Pham K et al (2015) VEGFR inhibitors upregulate CXCR4 in VEGF receptor-expressing glioblastoma in a TGFβR signaling-dependent manner. Cancer Lett 360: 60-67. doi:10.1016/j.canlet.2015.02.005
12. Stewart MW (2011) Aflibercept (VEGF-TRAP): the next anti-VEGF drug. Inflammation Allergy Drug Targets. 10:497-508.
13. of Wijngaarden P et al (2008) Inhibitors of vascular endothelial growth factor (VEGF) in the management of neovascular age-related macular degeneration: a review of current practice. Clin Exp Optom 91: 427-437
14. Zhang C et al (2012) Selective VEGFR inhibitors for anticancer therapeutics in clinical use and clinical trials. Curr Pharm Des 18: 2921-2935.

List of VEGFR inhibitors known so far and/or still in clinical trials:

• Acrizanib (LHA510): Acrizanib is an inhibitor of VEGFR-2 with an IC50 value of 17.4 nM in BaF3 Tel KDR cells.
• AEE788 (NVP-AEE788): AEE788 (NVP-AEE788) is a strong inhibitor of EGFR and HER2 / ErbB2 with IC50 of 2 nM and 6 nM, less effective against VEGFR2 / KDR, c-Abl, c-Src and Flt- 1 inhibits Ins-R, IGF-1R, PKC & agr; and CDK1 does not. Phase 1/2.
• Altiratinib: Altiratinib is an effective single-site nanomolar inhibitor of TRK, MET, TIE2 and VEGFR2 kinases with IC50 Vaults of 0.9 nM, 4.6 nM and 0.8 nM for TRKA, B and C, respectively. It inhibits MET and MET mutants with IC 50 Vaults in the range of 0.3-6 nM.
• Anlotinib (AL3818) -Dihydrochloride: Anlotinib (AL3818) is a highly effective and selective VEGFR2 inhibitor with an IC50 value of less than 1 nM. It has a broad antitumour potential in clinical studies.
• Apatinib: Apatinib is a highly potent and selective VEGFR-2 inhibitor. Clinical studies are available on gastric carcinoma.
• Axitinib: Axitinib (AG 013736) is a multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFRβ and c-Kit with IC50 of 0.1 nM, 0.2 nM, 0.1-0.3 nM, 1.6 nM and 1.7 nM in porcine aorta endothelial cells.
• AZD2932: AZD2932 is a potent and multi-targeted protein tyrosine kinase inhibitor with IC50 values of 8 nM, 4 nM, 7 nM and 9 nM for VEGFR-2, PDGFRβ, Flt-3 and c-Kit respectively.
• BAW2881 (NVP-BAW2881): BAW2881 (NVP-BAW2881) is a novel vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor that effectively inhibits VEGFR1-3 at concentrations of 1.0 to 4.3 nanomolar (nM) and inhibits PDGFRβ, c-Kit and RET at 45-72 nM concentrations. WHI-P180
• Bevacizumab (Anti-VEGF): Bevacizumab (Anti-VEGF, Avastin) is a humanized anti-VEGF monoclonal antibody that binds to and neutralizes all human VEGF-A isoforms and bioactive proteolytic fragments, MW: 149 KD.
• BFH772: BFH772 is a novel potent oral VEGFR2 inhibitor targeting VEGFR2 kinase with IC50 of 3 nM.
• BMS-794833: BMS-794833 is a potent ATP-competitive inhibitor of Met / VEGFR2 with IC50 of 1.7 nM / 15 nM, also inhibits Ron, Axl and Flt3 with IC50 of <3 nM; a prodrug of BMS-817378. phase 1.
• Brivanib (BMS-540215): Brivanib is an ATP-competitive inhibitor against VEGFR2 with an IC50 of 25 nM, moderate efficacy against VEGFR-1 and FGFR-1, but> 240-fold against PDGFR-β. Phase 3.
• Brivanib alaninate (BMS-582664): Brivanib alaninate (BMS-582664) is the prodrug of BMS-540215, an ATP-competitive inhibitor against VEGFR2 with IC50 of 25 nM.
• Cabozantinib (BMS-907351): Cabozantinib (XL184, BMS-907351) is a strong VEGFR2 inhibitor with an IC50 value of 0.035 nM and inhibits with IC50 also c-Met, Ret, Kit, Flt-1/3/4, Tie2 and AXL of 1.3 nM, 4 nM, 4.6 nM, 12 nM / 11.3 nM / 6 nM, 14.3 nM and 7 nM in cell-free assays. Cabozantinib induces PUMA-dependent apoptosis in colon cancer cells via the AKT / GSK-3β / NF-κB signalling pathway.
• Cabozantinib malate (XL184): Cabozantinib malate (XL184) is the malate of cabozantinib, a potent VEGFR2 inhibitor with an IC50 of 0.035 nM, and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2 and AXL with IC 50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM / 11.3 nM / 6 nM, 14.3 nM and 7 nM in cell-free assays. Cabozantinib malate (XL184) induces apoptosis.
• Cediranib (AZD2171): Cediranib (AZD2171, NSC-732208) is a highly effective VEGFR (KDR) inhibitor with IC50 of <1 nM, also inhibits Flt1 / 4 with IC50 of 5 nM / ≤3 nM, similar activity against c-Kit and PDGFRβ, 36, 110 and > 1000-fold more selective for VEGFR than PDGFR-α, CSF-1R and Flt3 in HUVEC cells. Cediranib (AZD2171) induces an accumulation of autophagic vacuoles. Phase 3.
• Cediranib maleate: Cediranib maleate (AZD-2171) is the maleate salt of cediranib, which is a strong inhibitor of VEGFR with IC50 of <1 nM and also inhibits Flt1 / 4 with IC50 of 5 nM / ≤3 nM
• Chlorine SU5416, Chlorine semaxanib: is a low molecular weight receptor tyrosine kinase (RTK) inhibitor of VEGFR-2, c-kit and both wild type and mutant FLT3. SU5416 also inhibits RET with IC50 of 170 nM. SU5416 reduces cell proliferation and induces apoptosis.
• CYC116: CYC116 is a strong inhibitor of Aurora A / B with a Ki of 8.0 nM / 9.2 nM, is less effective against VEGFR2 (Ki of 44 nM) and has 50 times higher efficacy than CDKs that are not active against PKA, Akt / PKB , PKC, no effect on GSK-3α / β, CK2, Plk1 and SAPK2A. Phase 1.
• Donafenib (Sorafenib D3): Sorafenib D3 (Bay 43-9006 D3) is the deuterium called sorafenib. Sorafenib is a multi-kinase inhibitor IC50 of 6 nM, 15 nM, 20 nM and 22 nM for Raf-1, mVEGFR-2, mVEGFR-3 and B-RAF respectively.
• Dovitinib (TKI258) Lactate: Dovitinib (TKI258) lactate is the lactate of dovitinib, a multitargeted RTK inhibitor, mainly for class III (FLT3 / c-Kit) with IC50 of 1 nM / 2 nM, also effective for class IV ( FGFR1 / 3) and class V (VEGFR1-4) RTKs with IC50 of 8-13 nM, less effective against InsR, EGFR, c-Met, EphA2, Tie2, IGFR1 and HER2. Phase 4.
• Dovitinib (TKI-258): Dovitinib (TKI258, CHIR258) is a multitargeted RTK inhibitor, mainly for class III (FLT3 / c-Kit) with IC50 of 1 nM / 2 nM, also effective against class IV (FGFR1 / 3) and class V (VEGFR1-4) RTKs with IC50 of 8-13 nM, less effective against InsR, EGFR, c-Met, EphA2, Tie2, IGF-1R and HER2 in cell-free assays. Phase 4.
• ENMD-2076 L - (+) - tartaric acid: ENMD-2076 L - (+) - tartaric acid is the tartaric acid of ENMD-2076, selective activity against Aurora A and Flt3 with IC50 of 14 nM and 1.86 nM, 25 fold more selective for Aurora A than Aurora B and less effective for VEGFR2 / KDR and VEGFR3, FGFR1 and FGFR2 and PDGFRα. Phase 2.
• ENMD-2076: ENMD-2076 has selective activity against Aurora A and Flt3 with IC50 of 14 nM and 1.86 nM, 25 times more selective for Aurora A than over Aurora B and less effective for RET, SRC, NTRK1 / TRKA, CSF1R / FMS , VEGFR2 / KDR, FGFR and PDGFRα. ENMD-2076 inhibits the growth of a variety of human solid tumor and hematopoietic cancer cell lines with IC50 from 0.025 to 0.7 μM , inducing apoptosis and G2 / M phase stop. Phase 2.
• Erdafitinib (JNJ-42756493): Erdafitinib (JNJ-42756493) is an effective and selective oral bioavailable inhibitor of pan-fibroblast growth factor receptor (FGFR) with potential antineoplastic activity. Erdafitinib also binds to RET, CSF-1R, PDGFR-α / PDGFR-β, FLT4, KIT and VEGFR-2 and induces cellular apoptosis.
• Foretinib (GSK1363089): Foretinib (GSK1363089, EXEL-2880, XL-880) is an ATP-competitive inhibitor of HGFR and VEGFR, mainly for Met and KDR with IC50 of 0.4 nM and 0.9 nM in cell-free assays. Less effective against Ron, Flt-1/3/4, Kit, PDGFRα / β and Tie-2 and low activity against FGFR1 and EGFR. Phase 2.
• Fruquintinib (HMPL-013): Fruquintinib is a low molecular weight inhibitor with strong activity and high selectivity against the VEGFR family. It inhibits VEGFR 1, 2, 3 with IC 50 values of 33 nM, 35 nM and 0.5 nM respectively and shows only weak inhibition of RET, FGFR-1 and c-kit kinases.
• Golvatinib (E7050): Golvatinib (E7050) is a dual c-Met and VEGFR-2 inhibitor with IC50 values of 14 nM and 16 nM and does not inhibit HUVEC growth stimulated by bFGF (up to 1000 nM). Phase 1/2.
• Ki8751: Ki8751 is an effective and selective inhibitor of VEGFR2 with an IC50 value of 0.9 nM, which is 40-fold more selective for VEGFR2 than c-Kit, PDGFRα and FGFR-2, and less active for EGFR, HGFR and InsR.
• KRN 633: KRN 633 is an ATP-competitive inhibitor of VEGFR1 / 2/3 with an IC50 value of 170 nM / 160 nM / 125 nM, inhibits PDGFR-α / β weakly and c-Kit does not block phosphorylation of FGFR-1, EGFR or c-Met in the cell.
• Lenalidomide (CC-5013): Lenalidomide (CC-5013) is a TNF-α secretion inhibitor with IC50 of 13 nM in PBMCs. Lenalidomide (CC-5013) is a ligand of the ubiquitin E3 ligase cereblon (CRBN) and causes selective ubiquitination and degradation of two lymphoid transcription factors, ICZF1 and ICZF3, by the CRBN-CRL4 ubiquitin ligase. Lenalidomide promotes cleaved caspase-3 expression and inhibits VEGF expression and induces apoptosis.
• Lenvatinib (E7080): Lenvatinib (E7080) is a multi-target inhibitor, mainly for VEGFR2 (KDR) / VEGFR3 (Flt-4) with IC50 of 4 nM / 5.2 nM, less effective against VEGFR1 / Flt-1, ~ 10-fold more selective for VEGFR2 / 3 against FGFR1, PDGFRα / β in cell-free assays. Lenvatinib (E7080) also inhibits FGFR1-4, PDGFR, KIT, RET and shows strong antitumor activity. Phase 3.
• Lenvatinib mesylate: Lenvatinib mesylate is a synthetic, orally available tyrosine kinase inhibitor that rearranges vascular endothelial growth factor receptor (VEGFR1-3), fibroblast growth factor receptor (FGFR1-4), platelet-derived growth factor receptor α (PDGFRα) and stem cell inhibits factor receptor (KIT) and during transfection (RET). Lenvatinib mesylate has potential antineoplastic activity.
• Linifanib (ABT-869): Linifanib (ABT-869, AL39324, RG3635) is a new, potent ATP-competitive VEGFR / PDGFR inhibitor for KDR, CSF-1R, Flt-1/3 and PDGFRβ with IC50 of 4 nM, 3 nM, 3 nM / 4 nM and 66 nM respectively, mostly effective in mutant kinase-dependent cancer cells (i.e. FLT3). Linifanib (ABT-869) induces autophagy and apoptosis. Phase 3.
• LY2874455: LY2874455 is a pan-FGFR inhibitor with an IC 50 value of 2.8 nM, 2.6 nM, 6.4 nM and 6 nM for FGFR1, FGFR2, FGFR3 and FGFR4 respectively and also inhibits VEGFR2 activity with an IC 50 value of 7 nM. Phase 1.
• MGCD-265 analogue: MGCD-265 is a potent multi-target and ATP-competitive inhibitor of c-Met and VEGFR1 / 2/3 with an IC50 value of 1 nM or 3 nM / 3 nM / 4 nM; also inhibits Ron and Tie2. Phase 1/2.
• Motesanib (AMG-706): Motesanib (AMG-706) is an orally bioavailable receptor tyrosine kinase inhibitor with IC50 values of 2 nM, 3 nM, 6 nM, 8 nM, 84 nM, 59 nM for VEGFR1, VEGFR2, VEGFR3, Kit , PDGFR and Ret.
• Motesanib diphosphate (AMG-706): Motesanib diphosphate (AMG-706) is a strong ATP-competitive inhibitor of VEGFR1 / 2/3 with an IC 50 value of 2 nM / 3 nM / 6 nM; similar activity against Kit, ~ 10 times more selective for VEGFR than PDGFR and Ret. Phase 3.
• Ningetinib: Ningetinib is an effective, orally bioavailable inhibitor of tyrosine kinase with an IC 50 value of 6.7 nM, 1.9 nM and <1.0 nM for c-Met, VEGFR2 and Axl respectively. Ningetinib shows antitumour activity.
• Nintedanib (BIBF 1120): Nintedanib (BIBF 1120, Intedanib, Vargatef, Ofev) is an effective triple angiokinase inhibitor for VEGFR1 / 2/3, FGFR1 / 2/3 and PDGFRα / β with an IC50 value of 34 nM / 13 nM / 13 nM 69 nM / 37 nM / 108 nM and 59 nM / 65 nM in cell-free assays. Phase 3.
• Nintedanib ethanesulfonate salt: Nintedanib is a low molecular weight tyrosine kinase inhibitor with an IC 50 value of 34 nM / 13 nM / 13 nM, 69 nM / 37 nM / 108 nM and 59 nM / 65 nM for VEGFR1 / 2/3, FGFR1 / 2 / 3 and PDGFRα / β.
• OSI-930: OSI-930 is a strong inhibitor of Kit, KDR and CSF-1R with an IC 50 value of 80 nM, 9 nM or 15 nM; also effective against Flt-1, c-Raf and Lck and low activity against PDGFRα / β, Flt-3 and abl. phase 1.
• Pazopanib HCl (GW786034 HCl): Pazopanib HCl (GW786034 HCl) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM, 140 nM or 146 nM in cell-free assays. Pazopanib induces autophagic type II cell death.
• Pazopanib: Pazopanib (GW786034) is a novel multi-target inhibitor of VEGFR1, VEGFR2, VEGFR3, PDGFR, FGFR, c-Kit and c-Fms / CSF1R with IC50 of 10 nM, 30 nM, 47 nM, 84 nM, 74 nM 140 nM or 146 nM in cell-free assays. Pazopanib induces activation of cathepsin B and autophagy.
• PDGFR Inhibitor 1: PDGFR Inhibitor 1 is an orally bioavailable switch pocket control inhibitor of wild-type and mutant forms of KIT and PDGFR with potential antineoplastic activity. It also inhibits several other kinases, including VEGFR2, TIE2, PDGFR-beta and CSF1R, further inhibiting tumor cell growth.
• Ponatinib (AP24534): Ponatinib (AP24534) is a novel, potent multi-target inhibitor of Abl, PDGFRα, VEGFR2, FGFR1 and Src with IC50 of 0.37 nM, 1.1 nM, 1.5 nM, 2.2 nM and 5.4 nM in cell-free assays, respectively. Ponatinib (AP24534) inhibits autophagy.
• PP121: PP-121 is a multi-targeting inhibitor of PDGFR, Hck, mTOR, VEGFR2, Src and Abl with IC50 of 2 nM, 8 nM, 10 nM, 12 nM, 14 nM and 18 nM, which also inhibits DNA-PK with IC 50 of 60 nM.
• RAF265 (CHIR-265): RAF265 (CHIR-265) is a strong selective inhibitor of C-Raf / B-Raf / B-Raf V600E with IC50 of 3-60 nM and shows strong inhibition of VEGFR2 phosphorylation with EC50 of 30 nM in cell-free assays. RAF265 (CHIR-265) induces cell cycle arrest and apoptosis. Phase 2.
• Ramucirumab (anti-VEGFR2): Ramucirumab is an IgG1 class monoclonal antibody that binds to VEGF-R2 and prevents its activation. The IC 50 value for blocking KDR binding to VEGF is 0.8 nM for ramucirumab, MW: 143.6 KD.
• Regorafenib (BAY 73-4506): Regorafenib (BAY 73-4506, Fluor-Sorafenib) is a multi-target inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRβ, Kit, RET and Raf-1 with IC50 of 13 nM / 4.2 nM / 46 nM, 22 nM, 7 nM, 1.5 nM or 2.5 nM in cell-free assays. Regorafenib induces autophagy.
• Regorafenib monohydrate: Regorafenib is a novel oral multi-kinase inhibitor with IC50 values of 13, 4.2, 46, 22, 7, 1.5, 2.5, 28, 19 nM for VEGFR1, murine VEGFR2, murine VEGFR3, PDGFR-β, KIT, RET, RAF -1, B-RAF or B-RAF (V600E).
• SAR131675: SAR131675 is a VEGFR3 inhibitor with IC50 / Ki of 23 nM / 12 nM in cell-free assays, about 50 and 10 times more selective for VEGFR3 than VEGFR1 / 2, low activity against Akt1, CDKs, PLK1, EGFR, IGF-1R, c-Met, Flt2 etc.
• Semaxanib (SU5416): Semaxanib (SU5416) is a potent and selective VEGFR (Flk-1 / KDR) inhibitor with an IC50 of 1.23 μM, 20 times more selective for VEGFR than PDGFRβ, low activity against EGFR, InsR and FGFR. Phase 3.
• SGI-7079: SGI-7079, a novel selective Axl inhibitor with an IC50 of 58 nM in vitro, inhibits tumor growth in a dose-dependent manner and is a potential therapeutic target for overcoming resistance to EGFR inhibitors.
• Sitravatinib (MGCD516): Sitravatinib (MGCD516) is a novel small molecule inhibitor targeting several RTKs involved in sarcoma cell growth, including c-Kit, PDGFRβ, PDGFRα, c-Met and Axl.
• SKLB 610: SKLB-610 is a multi-target inhibitor of tyrosine kinases. It is most effective against VEGFR2 and shows a slightly weaker inhibitor of FGFR2 and PDGFR.
• Sorafenib: Sorafenib (BAY 43-9006) is a multi-target inhibitor of Raf-1 and B-Raf with an IC 50 value of 6 nM and 22 nM in cell-free assays, respectively. Sorafenib inhibits VEGFR-2, VEGFR-3, PDGFR-β, Flt-3 and c-KIT with an IC 50 value of 90 nM, 20 nM, 57 nM, 59 nM or 68 nM. Sorafenib induces autophagy and apoptosis and activates ferroptosis with antitumour activity.
• Sorafenib tosylate: Sorafenib tosylate (Bay 43-9006) is a multi-kinase inhibitor of Raf-1 and B-Raf with an IC 50 value of 6 nM and 22 nM in cell-free assays, respectively. Sorafenib tosylate inhibits VEGFR-2, VEGFR-3, PDGFR-β, Flt-3 and c-KIT with an IC 50 value of 90 nM, 20 nM, 57 nM, 59 nM and 68 nM respectively. Sorafenib Tosylate induces autophagy and apoptosis and activates ferroptosis with antitumour activity.
• SU1498: SU1498, a strong inhibitor of KDR (IC50 = 0.7 μM), stimulates the accumulation of phosphorylated ERK1 / 2 in endothelial cells.
• SU5402: SU5402 is a potent multi-targeting receptor tyrosine kinase inhibitor with IC50 values of 20 nM, 30 nM and 510 nM for VEGFR2, FGFR1 and PDGF-Rβ respectively.
• Sulfatinib: Sulfatinib is an effective and highly selective tyrosine kinase inhibitor against VEGFR1, VEGFR2, VEGFR3, FGFR1 and CSF1R with an IC50 of 2 nM, 24 nM, 1 nM, 15 nM and 4 nM respectively. Sulfatinib shows encouraging antitumor activity and manageable toxicities in patients with advanced NETs.
• Sunitinib: Sunitinib (SU11248) is a multi-targeting RTK inhibitor that targets VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM and also inhibits the c-kit. Sunitinib is also a dose-dependent inhibitor of the autophosphorylation activity of IRE1α. Sunitinib induces autophagy and apoptosis.
• Sunitinib malate: Sunitinib malate is a multi-targeting RTK inhibitor that targets VEGFR2 (Flk-1) and PDGFRβ with IC50 of 80 nM and 2 nM in cell-free assays and also inhibits the c-Kit. Sunitinib Malate effectively inhibits the autophosphorylation of Ire1α Sunitinib Malate increases both the death receptor and mitochondria-dependent apoptosis.
• TAS-115: TAS-115 is a unique VEGFR / MET targeted inhibitor with an IC50 of 30 nM and 32 nM for rVEGFR2 and rMET respectively.
• Taxifolin (Dihydroquercetin): Taxifolin, type I inhibitor of VEGFR-2 kinase, is a flavonoid found in many plants such as Taxus chinensis, Siberian larch, Cedrus deodara and so on.
• Telatinib: Telatinib (BAY 57-9352) is a potent inhibitor of VEGFR2 / 3, c-Kit and PDGFRα with an IC 50 value of 6 nM / 4 nM, 1 nM and 15 nM respectively. Phase 2.
• Tivozanib (AV-951): Tivozanib (AV-951, KRN-951) is an effective and selective VEGFR inhibitor of VEGFR1 / 2/3 with an IC50 value of 30 nM / 6.5 nM / 15 nM and also inhibits PDGFR and c-Kit low activity against FGFR-1, Flt3, c-Met, EGFR and IGF-1R observed. Phase 3.
• Toceranibphosphate: Toceranibphosphate, the phosphate salt of toceranib, is a selective inhibitor of the tyrosine kinase activity of several members of the RTK family of split kinases, including Flk-1 / KDR, PDGFR and kit with Ki values of 6 nM and 5 nM for Flk-1 / KDR respectively PDGFRβ.
• Vandetanib (ZD6474): Vandetanib (ZD6474) is a potent inhibitor of VEGFR2 with an IC50 value of 40 nM in a cell-free assay. It also inhibits VEGFR3 and EGFR with IC50 of 110 nM or 500 nM. Not sensitive to PDGFRβ, Flt1, Tie-2 and FGFR1 with IC50 of 1.1-3.6 μM. No activity against MEK, CDK2, c-Kit, erbB2, FAK, PDK1, Akt and IGF-1R with IC 50 above 10 & mgr; M. vandetanib (ZD6474) increases apoptosis and induces autophagy by increasing the level of reactive oxygen species (ROS).
• Vatalanib (PTK787) 2HCl: Vatalanib 2HCl (PTK787, ZK 222584, cpg-79787) is an inhibitor of VEGFR2 / KDR with IC50 of 37 nM in a cell-free assay, less effective against VEGFR1 / Flt-1, 18-fold against VEGFR3 / Flt-4. phase 3.
• Vitamin E: Vitamin E (D-alpha-tocopherol) is a fat-soluble vitamin with strong antioxidant properties. It is a strong peroxyl radical scavenger and inhibits non-competitive cyclooxygenase activity in many tissues, also inhibits angiogenesis and tumor dormancy by suppressing gene transcription of vascular endothelial growth factor (VEGF).
• WHI-P180 is a multi-kinase inhibitor with IC50 values of 4.5 and 66 nM for the human protooncogene RET and the kinase insert domain receptor (KDR), respectively.
• X-82 (Vorolanib): Vorolanib is an oral multi-kinase double inhibitor of vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) with anti-angiogenic and antineoplastic activities.
• ZD-4190: ZD-4190 is a submicromolar inhibitor of VEGF-RTK activity in vitro with IC 50 values of 29 ± 4 nM and 708 ± 63 nM for KDR and Flt-1, respectively.
• ZM 306416: ZM 306416 (CB 676475) is a VEGFR (Flt and KDR) inhibitor for VEGFR1 with an IC50 value of 0,33 uM, which however also inhibits an EGFR inhibitor with an IC50 value of <10 nM.
• ZM 323881 HCl: ZM 323881 is a potent and selective VEGFR2 inhibitor with an IC50 value of <2 nM, almost no activity on VEGFR1, PDGFRβ, FGFR1, EGFR and ErbB2.
• 2-D08: 2-D08 (2 ', 3', 4'-trihydroxyflavone) is a cell-permeable, mechanistically unique inhibitor of protein sumoylation. It also inhibits Axl, IRAK4, ROS1, MLK4, GSK3β, RET, KDR and PI3Kα.