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Review

VEGFR-2 inhibitors and the therapeutic applications thereof: a patent review (2012-2016)

, , , &
Pages 987-1004 | Received 25 Aug 2016, Accepted 15 Jun 2017, Published online: 23 Jun 2017

References

  • Folkman J, D’Amore PA. Blood vessel formation: what is its molecular basis? Cell. 1996;87(7):1153–1155.
  • Risau W. Mechanism of angiogenesis. Nature. 1997;386(6626):671–674.
  • Gupta R, Tongers J, Losordo DW. Human studies of angiogenic gene therapy. Circ Res. 2009;105(8):724–736.
  • Chu H, Wang Y. Therapeutic angiogenesis: controlled delivery of angiogenic factors. Ther Deliv. 2012;3(6):693–714.
  • Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438(7070):967–974.
  • Markkanen JE, Rissanen TT, Kivelä A, et al. Growth factor-induced therapeutic angiogenesis and arteriogenesis in the heart-gene therapy. Cardiovasc Res. 2005;65(3):656–664.
  • Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 2004;9(Suppl 1):2–10.
  • Ivy SP, Wick JY, Kaufman BM. An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol. 2009;6(10):569–579.
  • Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–364.
  • Musumeci F, Radi M, Brullo C, et al. Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors. J Med Chem. 2012;55(24):10797–10822.
  • Neufeld G, Cohen T, Gengrinovitch S, et al. Vascular endothelial growth factor (VEGF) and its receptors. Faseb J. 1999;13(1):9–22.
  • Stuttfeld E, Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life. 2009;61(9):915–922.
  • Holmes K, Roberts OL, Thomas AM, et al. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007;19(10):2003–2012.
  • Roskoski R. VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Bioph Res Commun. 2008;375(3):287–291.
  • Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Biochem Soc Trans. 2012;31(1):20–24.
  • Smith NR, Baker D, James NH, et al. Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res. 2010;16(14):3548–3561.
  • Morabito A, Maio ED, Maio MD, et al. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions. Oncologist. 2006;11(7):753–764.
  • Huang L, Huang Z, Bai Z, et al. Development and strategies of VEGFR-2/KDR inhibitors. Future Med Chem. 2012;4(14):1839–1852.
  • Toubert ME, Vercellino L, Faugeron I, et al. Fatal heart failure after a 26-month combination of tyrosine kinase inhibitors in a papillary thyroid cancer. Thyroid. 2011 Apr;21(4):451–454.
  • Launay-Vacher V, Ayllon J, Janus N, et al. Evolution of renal function in patients treated with antiangiogenics after nephrectomy for renal cell carcinoma. Urol Oncol. 2011 Sep-Oct;29(5):492–494.
  • Ge J, Tan BX, Chen Y, et al. Interaction of green tea polyphenol epigallocatechin-3-gallate with sunitinib: potential risk of diminished sunitinib bioavailability. J Mol Med. 2011 Jun;89(6):595–602.
  • Iacovelli R, Palazzo A, Procopio G, et al. Incidence and relative risk of hepatic toxicity in patients treated with anti-angiogenic tyrosine kinase inhibitors for malignancy. Br J Clin Pharmacol. 2014 Jun;77(6):929–938.
  • Shea YF, Chiu WY, Mok MY, et al. Sunitinib-induced hyperammonaemia in a patient with pancreatic neuroendocrine tumour. J Clin Pharm Ther. 2013 Aug;38(4):327–329.
  • Ruinemans GM, Balemans C, Mattijssen V, et al. Fatal necrotizing pancreatitis during combined treatment with erlotinib and sunitinib. Lung Cancer. 2010 Dec;70(3):364–365.
  • Baldazzi V, Tassi R, Lapini A, et al. Sunitinib-induced hyperparathyroidism: a possible mechanism to altered bone homeostasis. Cancer. 2012 Jun 15;118(12):3165–3172.
  • Hong DS, Kurzrock R, Wheler JJ, et al. Phase I dose-escalation study of the multikinase inhibitor lenvatinib in patients with advanced solid tumors and in an expanded cohort of patients with melanoma. Clin Cancer Res. 2015 Nov 1;21(21):4801–4810.
  • Nakamichi S, Nokihara H, Yamamoto N, et al. A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2015 Dec;76(6):1153–1161.
  • Ascepion Pharmaceuticals, Inc. Deuterated heterocyclic compounds as kinase inhibitors and their preparation and use for the treatment of protein kinase-mediated diseases. WO2012028106. 2012.
  • Shanghai Institute of Pharmaceutical Industry. Arylurea compounds as protein kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of diseases. WO2012089137. 2012.
  • Shanghai Institute of Pharmaceutical Industry. Urea compounds as protein kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. WO2012139499. 2012.
  • Beta Pharma Canada Inc. Urea derivatives as protein kinase inhibitors and their preparation and use for the treatment of cancer. WO2012094451. 2012.
  • Hunan Nonferrous Metals Group Chembio Pharmacy Co., Ltd. N-((4-chloro-3-trifluoromethyl)phenyl)-n’-(2-fluoro-4-((2-hydroxymethylaminoformyl)-4-pyridyloxo)phenyl)urea and use thereof as anti-cancer drug. WO2013107225. 2013.
  • Hunan Nonferrous Metals Group Chembio Pharmacy Co., Ltd. Aromatic urea compounds as VEGFR-2 inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. WO2013037292. 2013.
  • Hunan Nonferrous Metals Group Chembio Pharmacy Co., Ltd. N-Substituted phenyl-N’-substituted heterocyclic urea compounds as VEGFR-2 kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. WO2014040243. 2014.
  • Allergan, Inc. Preparation of phenylacrylamides as PDGF and VEGF receptors kinase inhibitors. US20140256819. 2014.
  • Kala Pharmaceuticals, Inc. Urea derivatives as antiangiogenic agents. WO2014201127. 2014.
  • Allergan, Inc. Preparation of indole-1H-carboxamide derivatives as tyrosine kinase inhibitors. US20160096828. 2016
  • CrystalGenomics, Inc. Preparation of 2,3-dihydro-isoindol-1-one derivatives for treatment of diseases associated with abnormal or deregulated kinase activity. WO2012047017. 2012.
  • Nektar Therapeutics. Polymer-semaxanib moiety conjugates. WO2012088506. 2012.
  • Beta Pharma, Inc. New indolinone protein kinase inhibitors. WO2012139019. 2012.
  • Shijiazhuang Yiling Pharmaceutical Co., Ltd. Pyrrole-indolone derivatives as KDR kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of proliferative diseases. WO2015117551. 2015.
  • Hunan Nonferrous Metals Group Chembio Pharmacy Co., Ltd. Preparation of N-indole-1-carboxamide derivatives as antitumor agents. WO2013037293. 2013.
  • OriBase Pharma. Azaindole derivatives as multi kinase inhibitors and their preparation. WO2014102377. 2014.
  • KBP BioSciences Co., Ltd. Preparation of indole derivatives as tyrosine kinase inhibitors. WO2014086102. 2014.
  • Sunshine Lake Pharma Co., Ltd.; Calitor Sciences, LLC. Preparation of substituted quinoline compounds as protein tyrosine kinase modulators. US20120219522. 2012.
  • Tianjin Longbogen Pharmaceutical Co., Ltd. Aryloxyquinoline derivatives as protein tyrosine kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. WO2012171487. 2012.
  • Universita’ degli Studi di Padova. Biphenyl tricyclic quinazoline compounds as Tyrosine kinase inhibitors. WO2012127012. 2012.
  • Shenzhen Neptunus Pharmaceutical Co., Ltd. Heterocyclic compound of 4-amino quinazoline useful in treatment of cancer and its application. WO2014071824. 2014.
  • Universidade Federal do Rio de Janeiro. Preparation of 2-chloro-4-anilino-quinazoline derivs. as inhibitors of protein tyrosine kinases, especially EGFR and/or VEGFR-2, and their pharmaceutical compositions containing them. WO2014113859. 2014.
  • Kala Pharmaceuticals, Inc. Therapeutic compounds and uses in Cancer and eye disease therapy. WO2014127335. 2014.
  • Kala Pharmaceuticals, Inc. Preparation of quinoline and quinazoline derivatives useful in treating and/or preventing diseases. WO2014127214. 2014.
  • NeuPharma, Inc. Preparation of quinoxaline derivatives as BRAF mutant kinase inhibitors for treating cancer. WO2013040515. 2013.
  • NeuPharma, Inc. Preparation of quinoxalines as BRAF and KDR kinases inhibitors for treatment of cancer. WO2013112950. 2013.
  • Development Center for Biotechnology. Quinazoline compounds as kinase inhibitors. US20130165458. 2013.
  • Development Center for Biotechnology. Quinazoline compounds, method for preparing the same and use thereof. US20150158854. 2015.
  • Asinex Limited. Novel thiazolylamino-substituted heterocyclic kinase inhibitors and synthesis and antitumor activity. WO2012169934. 2012.
  • Boryung Pharmaceutical Co., Ltd. Nicotinamide derivative having angiogenesis inhibitory activity and method for the preparation thereof. WO2013015657. 2013.
  • MethylGene Inc. Preparation of benzoxazolyloxy thienopyridine derivatives as inhibitors of protein tyrosine kinase activity. US20130096136. 2013.
  • MethylGene Inc. Preparation of thienopyridines useful as PTK inhibitors in the treatment of disease such as ophthalmic disorders. WO2013044361. 2013.
  • MethylGene Inc. Preparation of thienopyridines useful as PTK inhibitors in the treatment of disease such as ophthalmic disorders. WO2013044362. 2013.
  • Cisen Pharmaceutical Co., Ltd.; Shanghai Institute of Pharmaceutical Industry. Benzazepine compounds as c-MET, VEGFR2, EGFR inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. WO2014029250. 2014.
  • Cisen Pharmaceutical Co., Ltd.; Shanghai Institute of Pharmaceutical Industry. Preparation of benazepine derivatives as antitumor agents. WO2014029251. 2014.
  • Hunan Nonferrous Metals Group Chembio Pharmacy Co., Ltd. Ureido-pyridinecarboxamide derivatives as VEGFR-2 inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. WO2014040242. 2014.
  • Allergan, Inc. Thienopyridine compounds as tyrosine kinase modulators and their preparation. US20140336108. 2014.
  • Cancer Research Technology Limited, UK; Institute of Cancer ResearchRoyal Cancer Hospital. The Preparation of 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 derivatives as RAF inhibitors for treating cancer. WO2015075483. 2015.
  • Hutchison MediPharma Enterprises Limited, Bahamas. Preparation of pyrimidine derivatives for treating angiogenesis-related disorders. US20080255172. 2008.
  • Kala Pharmaceuticals, Inc. Novel compounds and uses thereof. WO2014197313. 2014.
  • Allergan, Inc. Piperidylpyrimidine derivatives as modulators of protein kinase inhibitors and of vascular endothelial growth factor receptor 2. US9296747 (2016)
  • Cisen Pharmaceutical Co., Ltd.; Shanghai Institute of Pharmaceutical Industry. Pyrimidinobenzazepine compounds as kinase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of cancer. WO2014000686. 2014.
  • Cisen Pharmaceutical Co., Ltd.; Shanghai Institute of Pharmaceutical Industry. Preparation of fused ring containing pyrimidine or pyridine compounds as anti-tumor drugs. WO2014139458. 2014.
  • Novartis AG. Preparation of 5-[(pyrimidin-4-yl)oxy]-1H-indole-1-carboxamide derivatives as kinase inhibitors. WO2014184778. 2014.
  • Bionomics Limited. Preparation of 2,4,5-substituted pyrimidines as FAK and VEGFR3 inhibitors useful in treating proliferative diseases. WO2015123722. 2015.
  • Allergan, Inc. Kinase inhibitors. US9233968 (2016)
  • Allergan, Inc. Preparation of 7,8-dihydropyrido[4,3-d]pyrimidine derivatives as tyrosine kinase inhibitors. US20160096832. 2016.
  • Allergan, Inc. Preparation of pyrazolo[1,5-a]pyrido[3,4-e]pyrimidine derivatives as tyrosine kinase inhibitors. US20160096837. 2016.
  • Johannes Gutenberg-Universitaet Mainz. Conjugated 3-(indolyl)- and 3-(azaindolyl)-4-arylmaleimide compounds and their use in tumor treatment. WO2012084683. 2012.
  • New Hope R & D Bioscience, Inc. Preparation of oxetane dicarboxamide derivatives for use as protein kinase activity modulators. WO2013032797. 2013.
  • Jiangsu Simcere Pharmaceutical Co., Ltd. Fused heterocyclic derivatives and medical application. WO2013097753. 2013.
  • The Johns Hopkins University, Preparation of itraconazole analogs as inhibitors of VEGFR2 glycosylation and angiogenesis. WO2013036866. 2013.
  • Allergan, Inc. Preparation of phenylisothiazolecarboxamide derivatives for use as receptor tyrosine kinase (RTK) inhibitor. WO2013101954. 2013.
  • Angion Biomedica Corp. Preparation of pyrrolopyridines as anti-fibrotic compounds. WO2013112959. 2013.
  • KB Tumorforschungsgesellschaft mbH. Preparation of thioether derivatives as protein kinase inhibitors. WO2014079545. 2014.
  • Allergan, Inc. Preparation of nicotinamide derivatives for use as tyrosine kinase signal transduction modulators. WO2015089220. 2015.
  • TUBITAK. Phage display library-derived anti-human VEGFR2 antibodies and scFvs for treating angiogenesis-related disease and cancer. WO2012004631. 2012.
  • Vegenics Pty Limited. Vascular endothelial growth factor receptor-2-specific polypeptides of VEGF-D and VEGF-C and therapeutic uses thereof. WO2012088563. 2012.
  • National University of Singapore. Pericyte progenitors from peripheral blood. WO2012125123. 2012.
  • PharmAbcine Inc.; Samsung Life Public Welfare Foundation. Preparation of antibody fusion proteins with double-targeting properties. WO2012161372. 2012.
  • SNU R&DB Foundation. Preparation of Gremlin-1 antibody. WO2013137686. 2013.
  • Suzhou Institute of Nano-Tech and Nano-Bionics Sinano, CAS. Application of peptide targeting tumor VEGFR2. WO2014019520. 2014.
  • Kadmon Corporation, LLC. Human anti-VEGFR-2/KDR antibodies. WO2014055998. 2014.
  • PharmAbcine Inc. Dual-target antibody targeting VEGFR-2 and DLL4, and pharmaceutical composition comprising same. WO2014081202. 2014
  • Boston University. Therapeutic and research application of PDCL3. WO2016044219. 2016.
  • Kadmon Corporation, LLC. Human anti-VEGFR-2/KDR antibodies. WO2016057726. 2016.
  • Affibody AB. VEGFR-2 binding polypeptides. WO2016059057. 2016.
  • Dvorak HF. Angiogenesis: update 2005. J Thromb Haemost. 2005;3:1835–1842.
  • Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005;315:971–979.
  • Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer. 2008;8:579–591.
  • Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342.
  • Gragoudas ES, Adamis AP, Cunningham ET, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;351:2805–2816.
  • Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1419–1431.
  • Tang PA, Moore MJ. Aflibercept in the treatment of patients with metastatic colorectal cancer: latest findings and interpretations. Therap Adv Gastroenterol. 2013;6:459–473.
  • Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537–2548.
  • Wilke H, Muro K, Van CE, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014;15:1224–1235.
  • Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384:665–673.
  • Ferrara N, Adamis AP. Ten years of anti-vascular endothelial growth factor therapy. Nat Rev Drug Discov. 2016;15:385–403.
  • Shibuya M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J Biochem. 2013;153(1):13–19.
  • Jain RK, Duda DG, Willett CG, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol. 2009;6:327–338.

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