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ANGIOGENESIS AND AV-951: Angiogenesis as a process is very crucial for the progression of tumors. Not only cells proliferate uncontrollably in cancers, they require a better vascular system to support these new and upcoming cells. Hence the development of anti-angiogenesis compounds is seen as an attractive approach that can deal with one facet of tumor biology successfully. The most commonly linked pathway to angiogenesis is Vascular Endothelial Growth Factor (VEGF) pathway and the inhibition of this particular pathway at its receptor level has yielded promising results. There are many VEGF receptor (VEGFR) inhibitors that are being developed and tested in preclinical models and clinical trials and AV-951 VEGFR inhibitor is one of them that has shown potent inhibition of angiogenesis and tumor progression [1]. The best part of AG-951 pharmacology is that apart from VEGFR inhibition, its potency to inhibit c-Kit and PDGFR phosphorylation is also well documented. AG-951 PHARMACOLOGY AND PROPERTIES: AG-951 suppliers sell it under the brand name of Tivozanib also, and it is being developed by Aveo pharmaceutical company. The oral AV-951 PDGFR inhibitor is priced little high and AV-951 price for a 10 mg vial is around $200 and one can buy AV-951 easily for research and laboratory uses. AV-951 structure shows that is a quinoline urea derivative. AV-951 solubility is not found in water and ethanol but in DMSO, a 5 mg/ml solution can be made. When stored at -20oC, AV-951 stability is for 2 years. AV-951 IC50 against VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinase inhibition is 30 nM, 6.5 nM, and 15 nM, respectively. The IC50 values of AV-951 c-Kit inhibitor are 40 nM, 49 nM, 24 nM, 78 nM, and 78 nM for PDGFR-a, PDGFR-ß, EphB2, c-Kit, and Tie2 tyrosine kinases, respectively. THERAPEUTIC TESTING OF AV-591 AT VARIOUS LEVELS: The in vitro preclinical studies on AV-951 show its efficacy on blocking the proliferation and migration potential of endothelial cells, and in vivo studies with human tumor xenografts confirmed the same. AV-951 produced minimal toxicity in cancer patients and is under clinical trials for the treatment of renal cell carcinoma (RCC) and non-small cell lung (NSCL) carcinoma as a single agent, and in colorectal, breast, and other gastrointestinal tumors (GISTs) as a combination therapy. In athymic rat xenograft in vivo models of colon, hepatic, breast, lung, prostate, ovarian, and pancreatic tumors, AV-591 showed potent tumor growth inhibition [2]. The oral dose of AV-591 was decided in a clinical trial on patients with solid tumors from a study assessing its safety, pharmacodynamics and pharmacokinetics [3] after it showed success in treating solid tumors in athymic murine models [4]. 25% overall response rate and a progression-free survival of an year was observed in advanced renal cell carcinoma (RCC) patients upon treatment with AV-951 in a phase II clinical trial [4]. Apart from the success of AV-951 clinical trials, it has been patented for renal cell carcinoma (US2011/0118297 A1) patients and by Aveo pharmaceuticals for treatment of tumors (patent no US 7,736,861 B1). Various ongoing clinical trials involving AV-951 include studies from Aveo pharmaceuticals where its given in combination with Capecitabine A to solid tumor patients enrolled for a phase Ib trial assessing its maximum-tolerated dose (MTD) in these and in breast and colon cancer patients (NCT01306630). Another study from Aveo checks the synergistic effect of its combination with the traditional chemotherapeutic drug FOLFOX6 in patients suffering from advanced colorectal cancer (CRC) and gastrointestinal cancers in a phase I clinical trial (NCT00660153). Aveo is also checking its efficiency in renal cell carcinoma patients undergoing a phase 2 trial (NCT00502307). REFERENCS: 1. Campas, C.e.a., Tivozanib. Drugs of the Future, 2009. 2. Nakamura, K., et al, KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties. Cancer Res., 2006. 3. Eskens, F.E.e.a., Biological and Clinical Activity of Tivozanib, a Selective Inhibitor of VEGF Receptor-1, -2, and -3 Tyrosine Kinases, in a 4 Week on, 2 Week off Schedule in Patients With Advanced Solid Tumors. Clin Cancer Res, 2011. 4. De Luca, A.a.N., N., Tivozanib, a pan-VEGFR tyrosine kinase inhibitor for the potential treatment of solid tumors. IDrugs, 2010. Buy from the biotech company which is well known by scientists and drug discovery researchers worldwide for novel kinase inhibitors. Vist us to get more information regarding life reagents like Chemical Libraries, kinase inhibitor, kinase inhibitors, parp inhibitor, parp inhibitors more.
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