Vascular endothelial growth factor (VEGF) receptors: Drugs and new inhibitors

Journal of Medicinal Chemistry

Volumn 55, Issue 24, 2012, Pages 10797-10822

  Musumeci, Francesca ^a   Radi, Marco ^b   Brullo, Chiara ^a   Schenone, Silvia ^a  

^a UNIVERSITY OF GENOA   (Italy)

^b UNIVERSITY OF PARMA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; AXITINIB; BAY 579352; BRIVANIB; BRIVANIB ALANINATE; CABOZANTINIB; CEDIRANIB; DOVITINIB; FORETINIB; GEFITINIB; IMATINIB; LENVATINIB; MOTESANIB; NINTEDANIB; ORANTINIB; OSI 930; PAZOPANIB; RABEPRAZOLE; SORAFENIB; SUNITINIB; TELATINIB; TIVOZANIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VANDETANIB; VASCULOTROPIN INHIBITOR; VASCULOTROPIN RECEPTOR; VASCULOTROPIN RECEPTOR 1; VASCULOTROPIN RECEPTOR 2; VASCULOTROPIN RECEPTOR 3; VATALANIB;

ACUTE GRANULOCYTIC LEUKEMIA; ADVANCED CANCER; ANGIOGENESIS; ANTIPROLIFERATIVE ACTIVITY; BLOOD BRAIN BARRIER; BREAST CANCER; CANCER CHEMOTHERAPY; CANCER INVASION; CANCER SURVIVAL; CELL SURVIVAL; CHONDROSARCOMA; CHRONIC MYELOID LEUKEMIA; COLON CANCER; COLORECTAL CANCER; DIARRHEA; DRUG ABSORPTION; DRUG HALF LIFE; DRUG SOLUBILITY; DRUG STRUCTURE; FATIGUE; GASTROINTESTINAL STROMAL TUMOR; GLIOBLASTOMA; HEMATOLOGIC MALIGNANCY; HUMAN; HYDROGEN BOND; HYPERTENSION; KIDNEY CARCINOMA; LIVER CELL CARCINOMA; LIVER METASTASIS; LUNG CANCER; LUNG CARCINOMA; LUNG METASTASIS; LUNG NON SMALL CELL CANCER; LYMPH NODE METASTASIS; MELANOMA; MESOTHELIOMA; METASTASIS; MONOTHERAPY; NONHUMAN; OVARY CANCER; OVERALL SURVIVAL; PANCREAS CANCER; PROGRESSION FREE SURVIVAL; PROSTATE CANCER; RECOMMENDED DRUG DOSE; RECURRENT CANCER; REVIEW; SIGNAL TRANSDUCTION; SOLID TUMOR; STOMACH CANCER; STRUCTURE ACTIVITY RELATION; THYROID MEDULLARY CARCINOMA; TIME TO MAXIMUM PLASMA CONCENTRATION; UNSPECIFIED SIDE EFFECT;

ANGIOGENESIS INHIBITORS; ANIMALS; CLINICAL TRIALS AS TOPIC; HUMANS; MODELS, MOLECULAR; NEOPLASMS; PYRIDINES; PYRIMIDINES; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84871641406     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm301085w     Document Type: Review

References (211)

1. Folkman, J.; D'Amore, P. Blood vessel formation: what is its molecular basis? Cell 1996, 87, 1153-1155 (Pubitemid 27010098)
2. Risau, W. Mechanisms of angiogenesis Nature 1997, 386, 671-674 (Pubitemid 27193480)
3. Klagsbrun, M.; Moses, M. A. Molecular angiogenesis Chem. Biol. 1999, 6, R217-R224
4. Ivy, S. P.; Wick, J. Y.; Kaufman, B. M. An overview of small-molecule inhibitors of VEGFR signalling Nat. Rev. Clin. Oncol. 2009, 6, 569-579
5. Ferrara, N. Vascular endothelial growth factor as a target for anticancer therapy Oncologist 2004, 9, 2-10 (Pubitemid 38747842)
6. Potente, M.; Gerhardt, H.; Carmeliet, P. Basic and therapeutic aspects of angiogenesis Cell 2011, 146, 873-887
7. Folkman, J. Tumor angiogenesis: therapeutic implications N. Engl. J. Med. 1971, 285, 1182-1186
8. Hanahan, D.; Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis Cell 1996, 86, 353-364 (Pubitemid 26272076)
9. Kerbel, R. S. Tumor angiogenesis: past, present and the near future Carcinogenesis 2000, 21, 501-515
10. Sharpe, E. E.; Maupin, A. B.; Teleron, A. A.; Pyle, A. L.; Carmeliet, P.; Young, P. P. VEGF and PIGF promote adult vasculogenesis by enhancing EPC recruitment and vessel formation at the site of tumor neovascularisation FASEB J. 2006, 20, 1495-1497
11. Carmeliet, P. Angiogenesis in life, disease and medicine Nature 2005, 438, 932-936 (Pubitemid 43093958)
12. Leung, D. W.; Cachianes, G.; Kuang, W. J.; Goeddel, D. V.; Ferrara, N. Vascular endothelial growth factor is a secreted angiogenic mitogen Science 1989, 246, 1306-1309 (Pubitemid 20066716)
13. Holmes, K.; Roberts, O. L.; Thomas, A. M.; Cross, M. J. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition Cell. Signalling 2007, 19, 2003-2012 (Pubitemid 47354167)
14. Stuttfeld, E.; Ballmer-Hofer, K. Structure and function of VEGF receptors IUBMB Life 2009, 61, 915-922
15. Roskoski, R., Jr. VEGF receptor protein-tyrosine kinases: structure and regulation Biochem. Biophys. Res. Commun. 2008, 375, 287-291
16. Koch, S.; Tugues, S.; Li, X.; Gualandi, L.; Claesson-Welsh, L. Signal transduction by vascular endothelial growth factor receptors Biochem. J. 2011, 437, 169-183
17. Morabito, A.; De Maio, E.; Di Maio, M.; Normanno, N.; Perrone, F. Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials: current status and future directions Oncologist 2006, 17, 753-764 (Pubitemid 44157563)
18. Kappert, K.; Peters, K. G.; Böhmer, F. D.; Ostman, A. Tyrosine phosphatases in vessel wall signaling Cardiovasc. Res. 2005, 65, 587-598 (Pubitemid 40138979)
19. Bruce, D.; Tan, P. H. Vascular endothelial growth factor receptors and the therapeutic targeting of angiogenesis in cancer: Where do we go from here? Cell Commun. Adhes. 2011, 18, 85-103
20. Wiesmann, C.; Fuh, G.; Christinger, H. W.; Eigenbrot, C.; Wells, J. A.; de Vos, A. M. Crystal structure at 1.7 Å resolution of VEGF in complex with domain 2 of the Flt-1 receptor Cell 1997, 91, 695-704 (Pubitemid 27513660)
21. Maharaj, A. S.; Saint-Geniez, M.; Maldonado, A. E.; D'Amore, P. A. Vascular endothelial growth factor localization in the adult Am. J. Pathol. 2006, 168, 639-648 (Pubitemid 43271161)
22. Shibuya, M. Tyrosine kinase receptor Flt/VEGFR family: its characterization related to angiogenesis and cancer Genes Cancer 2010, 1, 1119-1123
23. Rahimi, N. VEGFR-1 and VEGFR-2: two non-identical twins with a unique physiognomy Front. Biosci. 2006, 11, 818-829 (Pubitemid 43262905)
24. Carmeliet, P.; Moons, L.; Luttun, A.; Vincenti, V.; Compernolle, V.; De Mol, M.; Wu, Y.; Bono, F.; Devy, L.; Beck, H.; Scholz, D.; Acker, T.; Di Palma, T.; Dewerchin, M.; Noel, A.; Stalmans, I.; Barra, A.; Blacher, S.; Vandendriessche, T.; Ponten, A.; Eriksson, U.; Plate, K. H.; Foidart, J. M.; Schaper, W.; Charnock Jones, D. S.; Hicklin, D. J.; Herbert, J. M.; Collen, D.; Persico, M. G. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions Nat. Med. 2001, 7, 575-583 (Pubitemid 32448325)
25. Zhao, Q.; Egashira, K.; Hiasa, K.; Ishibashi, M.; Inoue, S.; Ohtani, K.; Tan, C.; Shibuya, M.; Takeshita, A.; Sunagawa, K. Essential role of vascular endothelial growth factor and Flt-1 signals in neointimal formation after periadventitial injury Arterioscler., Thromb., Vasc. Biol. 2004, 24, 2284-2289 (Pubitemid 39658030)
26. Jackson, M. W.; Roberts, J. S.; Heckford, S. E.; Ricciardelli, C.; Stahl, J.; Choong, C.; Horsfall, D. J.; Tilley, W. D. A potential autocrine role for vascular endothelial growth factor in prostate cancer Cancer Res. 2002, 62, 854-859 (Pubitemid 34126964)
27. Yang, A. D.; Camp, E. R.; Fan, F.; Shen, L.; Gray, M. J.; Liu, W.; Somcio, R.; Bauer, T. W.; Wu, Y.; Hicklin, D. J.; Ellis, L. M. Vascular endothelial growth factor receptor-1 activation mediates epithelial to mesenchymal transition in human pancreatic carcinoma cells Cancer Res. 2006, 66, 46-51 (Pubitemid 43166007)
28. Frank, N. Y.; Schatton, T.; Kim, S.; Zhan, Q.; Wilson, B. J.; Ma, J.; Saab, K. R.; Osherov, V.; Widlund, H. R.; Gasser, M.; Waaga-Gasser, A. M.; Kupper, T. S.; Murphy, G. F.; Frank, M. H. VEGFR-1 expressed by malignant melanoma-initiating cells is required for tumor growth Cancer Res. 2011, 71, 1474-1485
29. Roybal, J. D.; Zang, Y.; Ahn, Y. H.; Yang, Y.; Gibbons, D. L.; Baird, B. N.; Alvarez, C.; Thilaganathan, N.; Liu, D. D.; Saintigny, P.; Heymach, J. V.; Creighton, C. J.; Kurie, J. M. miR-200 Inhibits lung adenocarcinoma cell invasion and metastasis by targeting Flt1/VEGFR1 Mol Cancer Res. 2011, 9, 25-35
30. Kaplan, R. N.; Riba, R. D.; Zacharoulis, S.; Bramley, A. H.; Vincent, L.; Costa, C.; MacDonald, D. D.; Jin, D. K.; Shido, K.; Kerns, S. A.; Zhu, Z.; Hicklin, D.; Wu, Y.; Port, J. L.; Altorki, N.; Port, E. R.; Ruggero, D.; Shmelkov, S. V.; Jensen, K. K.; Rafii, S.; Lyden, D. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche Nature 2005, 438, 820-827 (Pubitemid 41753060)
31. Duda, D. G.; Jain, R. K. Premetastatic lung "niche": Is vascular endothelial growth factor receptor 1 activation required? Cancer Res. 2010, 70, 5670-5673
32. Wu, F. T.; Stefanini, M. O.; Mac Gabhann, F.; Kontos, C. D.; Annex, B. H.; Popel, A. S. A systems biology perspective on sVEGFR1: its biological function, pathogenic role and therapeutic use J. Cell. Mol. Med. 2010, 14, 528-552
33. Kowanetz, M.; Ferrara, N. Vascular endothelial growth factor signaling pathways: therapeutic perspective Clin. Cancer Res. 2006, 12, 5018-5022 (Pubitemid 44453326)
34. Wang, F. Q.; Barfield, E.; Dutta, S.; Pua, T.; Fishman, D. A. VEGFR-2 silencing by small interference RNA (siRNA) suppresses LPA-induced epithelial ovarian cancer (EOC) invasion Gynecol. Oncol. 2009, 15, 414-423
35. Rodríguez-Antona, C.; Pallares, J.; Montero-Conde, C.; Inglada-Pérez, L.; Castelblanco, E.; Landa, I.; Leskelä, S.; Leandro-García, L. J.; López-Jiménez, E.; Letón, R.; Cascón, A.; Lerma, E.; Martin, M. C.; Carralero, M. C.; Mauricio, D.; Cigudosa, J. C.; Matias-Guiu, X.; Robledo, M. Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis Endocr.-Relat. Cancer 2010, 17, 7-16
36. Graells, J.; Vinyals, A.; Figueras, A.; Llorens, A.; Moreno, A.; Marcoval, J.; Gonzalez, F. J.; Fabra, A. Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling J. Invest. Dermatol. 2004, 123, 1151-1161 (Pubitemid 39586840)
37. Blom, T.; Roselli, A.; Häyry, V.; Tynninen, O.; Wartiovaara, K.; Korja, M.; Nordfors, K.; Haapasalo, H.; Nupponen, N. N. Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive neuroectodermal tumors J. Neuro-Oncol. 2010, 97, 217-224
38. Smith, N. R.; Baker, D.; James, N. H.; Ratcliffe, K.; Jenkins, M.; Ashton, S. E.; Sproat, G.; Swann, R.; Gray, N.; Ryan, A.; Jürgensmeier, J. M.; Womack, C. 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, 3548-3561
39. Mäkinen, T.; Veikkola, T; Mustjoki, S.; Karpanen, T.; Catimel, B.; Nice, E. C.; Wise, L.; Mercer, A.; Kowalski, H.; Kerjaschki, D.; Stacker, S. A.; Achen, M. G.; Alitalo, K. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3 EMBO J. 2001, 20, 4762-4773 (Pubitemid 32848629)
40. Su, J. L.; Yen, C. J.; Chen, P. S.; Chuang, S. E.; Hong, C. C.; Kuo, I. H.; Chen, H. Y.; Hung, M. C.; Kuo, M. L. The role of the VEGF-C/VEGFR-3 axis in cancer progression Br. J. Cancer 2007, 96, 541-545
41. Achen, M. G.; Mann, G. B.; Stacker, S. A. Targeting lymphangiogenesis to prevent tumour metastasis Br. J. Cancer 2006, 94, 1355-1360 (Pubitemid 43772266)
42. Boyer, S. J. Small molecule inhibitors of KDR (VEGFR-2) kinase: an overview of structure activity relationships Curr. Top. Med. Chem. 2002, 2, 973-1000
43. Schenone, S.; Bondavalli, F.; Botta, M. Antiangiogenic agents: an update on small molecule VEGFR inhibitors Curr. Med. Chem. 2007, 14, 2495-2516 (Pubitemid 47618038)
44. Gille, J.; Heidenreich, R.; Pinter, A.; Schmitz, J.; Boehme, B.; Hicklin, D. J.; Henschler, R.; Breier, G. Simultaneous blockade of VEGFR-1 and VEGFR-2 activation is necessary to efficiently inhibit experimental melanoma growth and metastasis formation Int. J. Cancer. 2007, 120, 1899-908 (Pubitemid 46418365)
45. Ferrara, N.; Alitalo, K. Clinical applications of angiogenic growth factors and their inhibitors Nat. Med. 1999, 5, 1359-1364
46. Kanda, S.; Miyata, Y.; Kanetake, H.; Smithgall, T. E. Non-receptor protein-tyrosine kinases as molecular targets for antiangiogenic therapy Int. J. Mol. Med. 2007, 20, 113-121
47. Casanovas, O.; Hicklin, D. J.; Bergers, G.; Hanahan, D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors Cancer Cell 2005, 8, 299-309 (Pubitemid 41443415)
48. Shibuya, M. Vascular endothelial growth factor-dependent and -independent regulation of angiogenesis BMB Rep. 2008, 41, 278-286 (Pubitemid 351656921)
49. Manley, P. W.; Bold, G.; Bruggen, J.; Fendrich, G.; Furet, P.; Mestan, J.; Schnell, C.; Stolz, B.; Meyer, T.; Meyhack, B.; Stark, W.; Strauss, A.; Wood, J. Advances in the structural biology, design and clinical development of VEGF-R kinase inhibitors for the treatment of angiogenesis Biochim. Biophys. Acta 2004, 1697, 17-27 (Pubitemid 38326758)
50. Carmeliet, P.; Jain, R. K. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases Nat. Rev. Drug Discovery 2011, 10, 417-427
51. Rosen, L. S. VEGF-targeted therapy: therapeutic potential and recent advances Oncologist 2005, 10, 382-391 (Pubitemid 40993566)
52. Van der Veldt, A. A.; Lubberink, M.; Bahce, I.; Walraven, M.; de Boer, M. P.; Greuter, H. N.; Hendrikse, N. H.; Eriksson, J.; Windhorst, A. D.; Postmus, P. E.; Verheul, H. M.; Serné, E. H.; Lammertsma, A. A.; Smit, E. F. Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs Cancer Cell 2012, 21, 82-91
53. Kerbel, R. S. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science 2006, 312, 1171-1175 (Pubitemid 43801134)
54. Kerbel, R.; Folkman, J. Clinical translation of angiogenesis inhibitors Nat. Rev. Cancer 2002, 2, 727-739 (Pubitemid 37328908)
55. Schenone, S.; Brullo, C.; Botta, M. New opportunities to treat the T315I-Bcr-Abl mutant in chronic myeloid leukaemia: tyrosine kinase inhibitors and molecules that act by alternative mechanisms Curr. Med. Chem. 2010, 17, 1220-1245
56. Marx, J. Cancer research. Obstacle for promising cancer therapy Science 2002, 295, 1444 (Pubitemid 34173972)
57. Lee, S. L.; Rouhi, P.; Dahl Jensen, L.; Zhang, D.; Ji, H.; Hauptmann, G.; Ingham, P.; Cao, Y. Hypoxia-induced pathological angiogenesis mediates tumor cell dissemination, invasion, and metastasis in a zebrafish tumor model Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 19485-19490
58. Rapisarda, A.; Melillo, G. Overcoming disappointing results with antiangiogenic therapy by targeting hypoxia Nat. Rev. Clin. Oncol. 2012, 9, 378-390
59. Cheng, H.; Force, T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics Circ. Res. 2010, 106, 21-34
60. Jain, R. K.; Duda, D. G.; Clark, J. W.; Loeffler, J. S. Lessons from phase III clinical trials on anti-VEGF therapy for cancer Nat. Clin. Pract. Oncol. 2006, 3, 24-40 (Pubitemid 43108832)
61. Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer Nat. Rev. Drug Discovery 2006, 5, 835-844 (Pubitemid 44480537)
62. Woo, H. Y.; Heo, J. Sorafenib in liver cancer Exp. Opin. Pharmacother. 2012, 13, 1059-1067
63. Calvisi, D. F.; Ladu, S.; Gorden, A.; Farina, M.; Conner, E. A.; Lee, J. S.; Factor, V. M.; Thorgeirsson, S. S. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC Gastroenterology 2006, 130, 1117-1128
64. Gedaly, R.; Angulo, P.; Chen, C.; Creasy, K. T.; Spear, B. T.; Hundley, J.; Daily, M. F.; Shah, M.; Evers, B. M. The role of PI3K/mTOR inhibition in combination with sorafenib in hepatocellular carcinoma treatment Anticancer Res. 2012, 32, 2531-2536
65. Schenone, S.; Brullo, C.; Botta, M. Small molecules ATP-competitive inhibitors of FLT3: a chemical overview Curr. Med. Chem. 2008, 15, 3113-3132
66. Roskoski, R., Jr. Sunitinib: a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor Biochem. Biophys. Res. Commun. 2007, 356, 323-328 (Pubitemid 46452568)
67. Harris, P. A.; Boloor, A.; Cheung, M.; Kumar, R.; Crosby, R. M.; Davis-Ward, R. G.; Epperly, A. H.; Hinkle, K. W.; Hunter, R. N., 3rd; Johnson, J. H.; Knick, V. B.; Laudeman, C. P.; Luttrell, D. K.; Mook, R. A.; Nolte, R. T.; Rudolph, S. K.; Szewczyk, J. R.; Truesdale, A. T.; Veal, J. M.; Wang, L.; Stafford, J. A. Discovery of 5-[[4-[(2,3-dimethyl-2 H -indazol-6-yl)methylamino] -2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor J. Med. Chem. 2008, 51, 4632-4640
68. Bukowski, R. M.; Yasothan, U.; Kirkpatrick, P. Pazopanib Nat. Rev. Drug Discovery 2010, 9, 17-18
69. Morabito, A.; Piccirillo, M. C.; Costanzo, R.; Sandomenico, C.; Carillio, G.; Daniele, G.; Giordano, P.; Bryce, J.; Carotenuto, P.; La Rocca, A.; Di Maio, M.; Normanno, N.; Rocco, G.; Perrone, F. Vandetanib: an overview of its clinical development in NSCLC and other tumors Drugs Today 2010, 46, 683-698
70. Commander, H.; Whiteside, G.; Perry, C. Vandetanib: first global approval Drugs 2011, 71, 1355-1365
71. Knowles, P. P.; Murray-Rust, J.; Kjaer, S.; Scott, R. P.; Hanrahan, S.; Santoro, M.; Ibáñez, C. F.; McDonald, N. Q. Structure and chemical inhibition of the RET tyrosine kinase domain J. Biol. Chem. 2006, 281, 33577-33587 (Pubitemid 46036738)
72. Ho, T. H.; Jonasch, E. Axitinib in the treatment of metastatic renal cell carcinoma Future Oncol. 2011, 7, 1247-1253
73. Solowiej, J.; Bergqvist, S.; McTigue, M. A.; Marrone, T.; Quenzer, T.; Cobbs, M.; Ryan, K.; Kania, R. S.; Diehl, W.; Murray, B. W. Characterizing the effects of the juxtamembrane domain on vascular endothelial growth factor receptor-2 enzymatic activity, autophosphorylation, and inhibition by axitinib Biochemistry 2009, 48, 7019-7031
74. Schenone, S.; Brullo, C.; Musumeci, F.; Botta, M. Novel dual Src/Abl inhibitors for hematologic and solid malignancies Expert Opin. Invest. Drugs 2010, 19, 931-945
75. Wedge, S. R.; Kendrew, J.; Hennequin, L. F.; Valentine, P. J.; Barry, S. T.; Brave, S. R.; Smith, N. R.; James, N. H.; Dukes, M.; Curwen, J. O.; Chester, R.; Jackson, J. A.; Boffey, S. J.; Kilburn, L. L.; Barnett, S.; Richmond, G. H.; Wadsworth, P. F.; Walker, M.; Bigley, A. L.; Taylor, S. T.; Cooper, L.; Beck, S.; Jurgensmeier, J. M.; Ogilvie, D. J. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer Cancer Res. 2005, 65, 4389-4400 (Pubitemid 40775678)
76. Lindsay, C. R.; MacPherson, I. R.; Cassidy, J. Current status of cediranib: the rapid development of a novel anti-angiogenic therapy Future Oncol. 2009, 5, 421-432
77. Batchelor, T. T.; Duda, D. G.; di Tomaso, E.; Ancukiewicz, M.; Plotkin, S. R.; Gerstner, E.; Eichler, A. F.; Drappatz, J.; Hochberg, F. H.; Benner, T.; Louis, D. N.; Cohen, K. S.; Chea, H.; Exarhopoulos, A.; Loeffler, J. S.; Moses, M. A.; Ivy, P.; Sorensen, A. G.; Wen, P. Y.; Jain, R. K. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma J. Clin. Oncol. 2010, 28, 2817-2823
78. di Tomaso, E.; Snuderl, M.; Kamoun, W. S.; Duda, D. G.; Auluck, P. K.; Fazlollahi, L.; Andronesi, O. C.; Frosch, M. P.; Wen, P. Y.; Plotkin, S. R.; Hedley-Whyte, E. T.; Sorensen, A. G.; Batchelor, T. T.; Jain, R. K. Glioblastoma recurrence after cediranib therapy in patients: lack of "rebound" revascularization as mode of escape Cancer Res. 2011, 71, 19-28
79. Sorensen, A. G.; Emblem, K. E.; Polaskova, P.; Jennings, D.; Kim, H.; Ancukiewicz, M.; Wang, M.; Wen, P. Y.; Ivy, P.; Batchelor, T. T.; Jain, R. K. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion Cancer Res. 2012, 72, 402-407
80. Mulders, P.; Hawkins, R.; Nathan, P.; de Jong, I.; Osanto, S.; Porfiri, E.; Protheroe, A.; van Herpen, C. M.; Mookerjee, B.; Pike, L.; Jürgensmeier, J. M.; Gore, M. E. Cediranib monotherapy in patients with advanced renal cell carcinoma: results of a randomised phase II study Eur. J. Cancer 2012, 48, 527-537
81. Garland, L. L.; Chansky, K.; Wozniak, A. J.; Tsao, A. S.; Gadgeel, S. M.; Verschraegen, C. F.; Dasilva, M. A.; Redman, M.; Gandara, D. R. Phase II study of cediranib in patients with malignant pleural mesothelioma: SWOG S0509 J. Thorac. Oncol. 2011, 6, 1938-1945
82. Alberts, S. R.; Fitch, T. R.; Kim, G. P.; Morlan, B. W.; Dakhil, S. R.; Gross, H. M.; Nair, S. Cediranib (AZD2171) in patients with advanced hepatocellular carcinoma: a phase II north central cancer treatment troup clinical trial Am. J. Clin. Oncol. 2012, 35, 329-333
83. Fiedler, W.; Mesters, R.; Heuser, M.; Ehninger, G.; Berdel, W. E.; Zirrgiebel, U.; Robertson, J. D.; Puchalski, T. A.; Collins, B.; Jürgensmeier, J. M.; Serve, H. An open-label, phase I study of cediranib (RECENTIN) in patients with acute myeloid leukemia Leuk. Res. 2010, 34, 196-202
84. Yakes, F. M.; Chen, J.; Tan, J.; Yamaguchi, K.; Shi, Y.; Yu, P.; Qian, F.; Chu, F.; Bentzien, F.; Cancilla, B.; Orf, J.; You, A.; Laird, A. D.; Engst, S.; Lee, L.; Lesch, J.; Chou, Y. C.; Joly, A. H. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth Mol. Cancer Ther. 2011, 10, 2298-2308
85. Zhang, Y.; Guessous, F.; Kofman, A.; Schiff, D.; Abounader, R. XL-184, a MET, VEGFR-2 and RET kinase inhibitor for the treatment of thyroid cancer, glioblastoma multiforme and NSCLC IDrugs 2010, 13, 112-121
86. Bowles, D. W.; Kessler, E. R.; Jimeno, A. Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib) Drugs Today 2011, 47, 857-868
87. Durante, C.; Russo, D.; Verrienti, A.; Filetti, S. XL184 (cabozantinib) for medullary thyroid carcinoma Expert Opin. Invest. Drugs 2011, 20, 407-413
88. Qian, F.; Engst, S.; Yamaguchi, K.; Yu, P.; Won, K. A.; Mock, L.; Lou, T.; Tan, J.; Li, C.; Tam, D.; Lougheed, J.; Yakes, F. M.; Bentzien, F.; Xu, W.; Zaks, T.; Wooster, R.; Greshock, J.; Joly, A. H. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases Cancer Res. 2009, 69, 8009-8016
89. Zillhardt, M.; Park, S. M.; Romero, I. L.; Sawada, K.; Montag, A.; Krausz, T.; Yamada, S. D.; Peter, M. E.; Lengyel, E. Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis Clin. Cancer Res. 2011, 17, 4042-4051
90. Huynh, H.; Ong, R.; Soo, K. C. Foretinib demonstrates anti-tumor activity and improves overall survival in preclinical models of hepatocellular carcinoma Angiogenesis 2012, 15, 59-70
91. Eder, J. P.; Shapiro, G. I.; Appleman, L. J.; Zhu, A. X.; Miles, D.; Keer, H.; Cancilla, B.; Chu, F.; Hitchcock-Bryan, S.; Sherman, L.; McCallum, S.; Heath, E. I.; Boerner, S. A.; LoRusso, P. M. A phase I study of foretinib, a multi-targeted inhibitor of c-Met and vascular endothelial growth factor receptor 2 Clin. Cancer Res. 2010, 16, 3507-3516
92. Dumas, J. Protein kinase inhibitors from the urea class Curr. Opin. Drug Discovery Dev. 2002, 5, 718-727 (Pubitemid 36253791)
93. Nakamura, K.; Taguchi, E.; Miura, T.; Yamamoto, A.; Takahashi, K.; Bichat, F.; Guilbaud, N.; Hasegawa, K.; Kubo, K.; Fujiwara, Y.; Suzuki, R.; Kubo, K.; Shibuya, M.; Isoe, T. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties Cancer Res. 2006, 66, 9134-9142 (Pubitemid 44521133)
94. Eskens, F. A.; Planting, A.; Van Doorn, L.; Isoe, T.; Hayashi, K.; Hussain, S.; Ekman, L.; Burger, H.; Verweij, J. An open-label phase I dose escalation study of KRN951, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and 1 in a 4 week on, 2 week off schedule in patients with advanced solid tumors J. Clin. Oncol. 2006, 24, 2034; Asco Meeting Abstracts
95. De Luca, A.; Normanno, N. Tivozanib, a pan-VEGFR tyrosine kinase inhibitor for the potential treatment of solid tumors IDrugs 2010, 13, 636-645
96. Eskens, F. A.; de Jonge, M. J.; Bhargava, P.; Isoe, T.; Cotreau, M. M.; Esteves, B.; Hayashi, K.; Burger, H.; Thomeer, M.; van Doorn, L; Verweij, J. Biologic and clinical activity of tivozanib (AV-951, KRN-951), 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, 17, 7156-7163
97. Nosov, D. A.; Esteves, B.; Lipatov, O. N.; Lyulko, A. A.; Anischenko, A. A.; Chacko, R. T.; Doval, D. C.; Strahs, A.; Slichenmyer, W. J.; Bhargava, P. Antitumor activity and safety of tivozanib (AV-951) in a phase II randomized discontinuation trial in patients with renal cell carcinoma J. Clin. Oncol. 2012, 30, 1678-1685
98. Matsui, J.; Funahashi, Y.; Uenaka, T.; Watanabe, T.; Tsuruoka, A.; Asada, M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase Clin. Cancer Res. 2008, 14, 5459-5465
99. Ikuta, K.; Yano, S.; Trung, V. T.; Hanibuchi, M.; Goto, H.; Li, Q.; Wang, W.; Yamada, T.; Ogino, H.; Kakiuchi, S.; Uehara, H.; Sekido, Y.; Uenaka, T.; Nishioka, Y.; Sone, S. E7080, a multi-tyrosine kinase inhibitor, suppresses the progression of malignant pleural mesothelioma with different proangiogenic cytokine production profiles Clin. Cancer Res. 2009, 15, 7229-7237
100. Bruheim, S.; Kristian, A.; Uenaka, T.; Suo, Z.; Tsuruoka, A.; Nesland, J. M.; Fodstad, Ø. Antitumour activity of oral E7080, a novel inhibitor of multiple tyrosine kinases, in human sarcoma xenografts Int. J. Cancer 2011, 129, 742-750
101. Gild, M. L.; Bullock, M.; Robinson, B. G.; Clifton-Bligh, R. Multikinase inhibitors: a new option for the treatment of thyroid cancer Nat. Rev. Endocrinol. 2011, 7, 617-624
102. Yamada, K.; Yamamoto, N.; Yamada, Y.; Nokihara, H.; Fujiwara, Y.; Hirata, T.; Koizumi, F.; Nishio, K.; Koyama, N.; Tamura, T. Phase I dose-escalation study and biomarker analysis of E7080 in patients with advanced solid tumors Clin. Cancer Res. 2011, 17, 2528-2537
103. Boss, D. S.; Glen, H.; Beijnen, J. H.; Keesen, M.; Morrison, R.; Tait, B.; Copalu, W.; Mazur, A.; Wanders, J.; O'Brien, J. P.; Schellens, J. H.; Evans, T. R. A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours Br. J. Cancer 2012, 106, 1598-1604
104. Bello, E.; Colella, G.; Scarlato, V.; Oliva, P.; Berndt, A.; Valbusa, G.; Serra, S. C.; D'Incalci, M.; Cavalletti, E.; Giavazzi, R.; Damia, G.; Camboni, G. E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models Cancer Res. 2011, 71, 1396-1405
105. Sala, F.; Bagnati, R.; Livi, V.; Cereda, R.; D'Incalci, M.; Zucchetti, M. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the determination of the novel inhibitor of angiogenesis E-3810 in human plasma and its application in a clinical pharmacokinetic study J. Mass Spectrom. 2011, 46, 1039-1045
106. Cai, S.; Chou, J.; Harwood, E.; Machajewski, T. D.; Ryckman, D.; Shang, X.; Zhu, S. Preparation of Benzimidazole Quinolinones and Lactate Salts Thereof for Inhibiting Vascular Endothelial Growth Factor Receptor Tyrosine Kinase. WO 2005046589, 2005.
107. Renhowe, P. A.; Pecchi, S.; Shafer, C. M.; Machajewski, T. D.; Jazan, E. M.; Taylor, C.; Antonios-McCrea, W.; McBride, C. M.; Frazier, K.; Wiesmann, M.; Lapointe, G. R.; Feucht, P. H.; Warne, R. L.; Heise, C. C.; Menezes, D.; Aardalen, K.; Ye, H.; He, M.; Le, V.; Vora, J.; Jansen, J. M.; Wernette-Hammond, M. E.; Harris, A. L. Design, structure-activity relationships and in vivo characterization of 4-amino-3-benzimidazol-2-ylhydroquinolin-2-ones: a novel class of receptor tyrosine kinase inhibitors J. Med. Chem. 2009, 52, 278-292
108. Lee, S. H.; Lopes de Menezes, D.; Vora, J.; Harris, A.; Ye, H.; Nordahl, L.; Garrett, E.; Samara, E.; Aukerman, S. L.; Gelb, A. B.; Heise, C. In vivo target modulation and biological activity of CHIR-258, a multitargeted growth factor receptor kinase inhibitor, in colon cancer models Clin. Cancer Res. 2005, 11, 3633-3641 (Pubitemid 40685578)
109. Lopes de Menezes, D. E.; Peng, J.; Garrett, E. N.; Louie, S. G.; Lee, S. H.; Wiesmann, M.; Tang, Y.; Shephard, L.; Goldbeck, C.; Oei, Y.; Ye, H.; Aukerman, S. L.; Heise, C. CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia Clin. Cancer Res. 2005, 11, 5281-5291 (Pubitemid 41003717)
110. Xin, X.; Abrams, T. J.; Hollenbach, P. W.; Rendahl, K. G.; Tang, Y.; Oei, Y. A.; Embry, M. G.; Swinarski, D. E.; Garrett, E. N.; Pryer, N. K.; Trudel, S.; Jallal, B.; Mendel, D. B.; Heise, C. C. CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice Clin. Cancer Res. 2006, 12, 4908-4915 (Pubitemid 44338578)
111. Kim, K. B.; Chesney, J.; Robinson, D.; Gardner, H.; Shi, M. M.; Kirkwood, J. M. Phase I/II and pharmacodynamic study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma Clin. Cancer Res. 2011, 17, 7451-7461
112. Sun, L.; Tran, N.; Liang, C.; Tang, F.; Rice, A.; Schreck, R.; Waltz, K.; Shawver, L. K.; McMahon, G.; Tang, C. Design, synthesis, and evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases J. Med. Chem. 1999, 42, 5120-5130 (Pubitemid 30020263)
113. Ohta, M.; Kawabata, T.; Yamamoto, M.; Tanaka, T.; Kikuchi, H.; Hiramatsu, Y.; Kamiya, K.; Baba, M.; Konno, H. TSU68, an antiangiogenic receptor tyrosine kinase inhibitor, induces tumor vascular normalization in a human cancer xenograft nude mouse model Surg. Today 2009, 39, 1046-1053
114. Klenke, F. M.; Abdollahi, A.; Bertl, E.; Gebhard, M. M.; Ewerbeck, V.; Huber, P. E.; Sckell, A. Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo BMC Cancer 2007, 7, 49-56
115. Yamamoto, M.; Kikuchi, H.; Ohta, M.; Kawabata, T.; Hiramatsu, Y.; Kondo, K.; Baba, M.; Kamiya, K.; Tanaka, T.; Kitagawa, M.; Konno, H. TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche Cancer Res. 2008, 68, 9754-9762
116. Kanai, F.; Yoshida, H.; Tateishi, R.; Sato, S.; Kawabe, T.; Obi, S.; Kondo, Y.; Taniguchi, M.; Tagawa, K.; Ikeda, M.; Morizane, C.; Okusaka, T.; Arioka, H.; Shiina, S.; Omata, M. A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma Cancer Chemother. Pharmacol. 2011, 67, 315-324
117. Toi, M.; Saeki, T.; Iwata, H.; Inoue, K.; Tokuda, Y.; Sato, Y.; Ito, Y.; Aogi, K.; Takatsuka, Y.; Arioka, H. A multicenter phase II study of TSU-68, an oral multiple tyrosine kinase inhibitor, in combination with docetaxel in metastatic breast cancer patients with anthracycline resistance. Breast Cancer [Online early access]. DOI: 10.1007/s10147-012-0421-9. Published Online: Mar 2, 2012.
118. Roth, G. J.; Heckel, A.; Colbatzky, F.; Handschuh, S.; Kley, J.; Lehmann-Lintz, T.; Lotz, R.; Tontsch-Grunt, U.; Walter, R.; Hilberg, F. Design, synthesis, and evaluation of indolinones as triple angiokinase inhibitors and the discovery of a highly specific 6-methoxycarbonyl-substituted indolinone (BIBF 1120) J. Med. Chem. 2009, 52, 4466-4480
119. Hilberg, F.; Roth, G. J.; Krssak, M.; Kautschitsch, S.; Sommergruber, W.; Tontsch-Grunt, U.; Garin-Chesa, P.; Bader, G.; Zoephel, A.; Quant, J.; Heckel, A.; Rettig, W. J. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy Cancer Res. 2008, 68, 4774-4782
120. Ledermann, J. A.; Hackshaw, A.; Kaye, S.; Jayson, G.; Gabra, H.; McNeish, I.; Earl, H.; Perren, T.; Gore, M.; Persic, M.; Adams, M.; James, L.; Temple, G.; Merger, M.; Rustin, G. Randomized phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer J. Clin. Oncol. 2011, 29, 3798-3804
121. Santos, E. S.; Gomez, J. E.; Raez, L. E. Targeting angiogenesis from multiple pathways simultaneously: BIBF 1120, an investigational novel triple angiokinase inhibitor Invest. New Drugs 2012, 30, 1261-1269
122. Bold, G.; Altmann, K. H.; Frei, J.; Lang, M.; Manley, P. W.; Traxler, P.; Wietfeld, B.; Bruggen, J.; Buchdunger, E.; Cozens, R.; Ferrari, S.; Furet, P.; Hofmann, F.; Martiny-Baron, G.; Mestan, J.; Rosel, J.; Sills, M.; Stover, D.; Acemoglu, F.; Boss, E.; Emmenegger, R.; Lasser, L.; Masso, E.; Roth, R.; Schlachter, C.; Vetterli, W.; Wyss, D.; Wood, J. M. New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis J. Med. Chem. 2000, 43, 2310-2323 (Pubitemid 30431929)
123. Jahan, T.; Gu, L.; Kratzke, R.; Dudek, A.; Otterson, G. A.; Wang, X.; Green, M.; Vokes, E. E.; Kindler, H. L. Vatalanib in malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B (CALGB 30107) Lung Cancer 2012, 76, 393-396
124. Joensuu, H.; De Braud, F.; Grignagni, G.; De Pas, T.; Spitalieri, G.; Coco, P.; Spreafico, C.; Boselli, S.; Toffalorio, F.; Bono, P.; Jalava, T.; Kappeler, C.; Aglietta, M.; Laurent, D.; Casali, P. G. Vatalanib for metastatic gastrointestinal stromal tumour (GIST) resistant to imatinib: final results of a phase II study Br. J. Cancer 2011, 104, 1686-1690
125. Gauler, T. C.; Besse, B.; Mauguen, A.; Meric, J. B.; Gounant, V.; Fischer, B.; Overbeck, T. R.; Krissel, H.; Laurent, D.; Tiainen, M.; Commo, F.; Soria, J. C.; Eberhardt, W. E. Phase II trial of PTK787/ZK 222584 (vatalanib) administered orally once-daily or in two divided daily doses as second-line monotherapy in relapsed or progressing patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) Ann. Oncol. 2012, 23, 678-687
126. Cook, N.; Basu, B.; Biswas, S.; Kareclas, P.; Mann, C.; Palmer, C.; Thomas, A.; Nicholson, S.; Morgan, B.; Lomas, D.; Sirohi, B.; Mander, A. P.; Middleton, M.; Corrie, P. G. A phase 2 study of vatalanib in metastatic melanoma patients Eur. J. Cancer 2010, 46, 2671-2673
127. Sobrero, A. F.; Bruzzi, P. Vatalanib in advanced colorectal cancer: two studies with identical results J. Clin. Oncol. 2011, 29, 1938-1940
128. Dumas, J. P.; Hatoum-Mokdad, H. N.; Joe, T. K.; Kluender, H. C. E.; Lee, W.; Nagarathnam, D.; Sibley, R. N.; Su, N.; Boyer, S. J. Substituted Pyridazines and Fused Pyridazines with Angiogenesis Inhibting Activity. WO2001010859, 2001.
129. Eskens, F. A.; Steeghs, N.; Verweij, J.; Bloem, J. L.; Christensen, O.; van Doorn, L.; Ouwerkerk, J.; de Jonge, M. J.; Nortier, J. W.; Kraetzschmar, J.; Rajagopalan, P.; Gelderblom, H. Phase I dose escalation study of telatinib, a
130. Mross, K.; Frost, A.; Scheulen, M. E.; Krauss, J.; Strumberg, D.; Schultheiss, B.; Fasol, U.; Büchert, M.; Krätzschmer, J.; Delesen, H.; Rajagopalan, P.; Christensen, O. Phase I study of telatinib (BAY 57-9352): analysis of safety, pharmacokinetics, tumor efficacy, and biomarkers in patients with colorectal cancer Vasc. Cell 2011, 3, 16
131. Furet, P.; Bold, G.; Hofmann, F.; Manley, P.; Meyer, T.; Altmann, K. H. Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching Bioorg. Med. Chem. Lett. 2003, 13, 2967-2971 (Pubitemid 37006327)
132. Polverino, A.; Coxon, A.; Starnes, C.; Diaz, Z.; DeMelfi, T.; Wang, L.; Bready, J.; Estrada, J.; Cattley, R.; Kaufman, S.; Chen, D.; Gan, Y.; Kumar, G.; Meyer, J.; Neervannan, S.; Alva, G.; Talvenheimo, J.; Montestruque, S.; Tasker, A.; Patel, V.; Radinsky, R.; Kendall, R. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts Cancer Res. 2006, 66, 8715-8721 (Pubitemid 44449188)
133. Coxon, A.; Bush, T.; Saffran, D.; Kaufman, S.; Belmontes, B.; Rex, K.; Hughes, P.; Caenepeel, S.; Rottman, J. B.; Tasker, A.; Patel, V.; Kendall, R.; Radinsky, R.; Polverino, A. Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors Clin. Cancer Res. 2009, 15, 110-118
134. Coxon, A.; Bready, J.; Kaufman, S.; Estrada, J.; Osgood, T.; Canon, J.; Wang, L.; Radinsky, R.; Kendall, R.; Hughes, P.; Polverino, A. Anti-tumor activity of motesanib in a medullary thyroid cancer model J. Endocrinol. Invest. 2012, 35, 181-190
135. Benjamin, R. S.; Schöffski, P.; Hartmann, J. T.; Van Oosterom, A.; Bui, B. N.; Duyster, J.; Schuetze, S.; Blay, J. Y.; Reichardt, P.; Rosen, L. S.; Skubitz, K.; McCoy, S.; Sun, Y. N.; Stepan, D. E.; Baker, L. Efficacy and safety of motesanib, an oral inhibitor of VEGF, PDGF, and Kit receptors, in patients with imatinib-resistant gastrointestinal stromal tumors Cancer Chemother. Pharmacol. 2011, 68, 69-77
136. Raghav, K. P.; Blumenschein, G. R. Motesanib and advanced NSCLC: experiences and expectations Expert Opin. Invest. Drugs 2011, 20, 859-869
137. Wynne, G. M.; Doyle, K.; Ahmed, S.; Li, A.; Keily, J. F.; Rasamison, C.; Pegg, N. A.; Saba, I.; Thomas, C.; Smyth, D.; Sadiq, S.; Newton, G.; Dawson, G.; Crew, A. P.; Castelano, A. L. (2-Carboxamido) (3-Amino) Thiophene Compounds. WO2004063330, 2004.
138. Garton, A. J.; Crew, A. P.; Franklin, M.; Cooke, A. R.; Wynne, G. M.; Castaldo, L.; Kahler, J.; Winski, S. L.; Franks, A.; Brown, E. N.; Bittner, M. A.; Keily, J. F.; Briner, P.; Hidden, C.; Srebernak, M. C.; Pirrit, C.; O'Connor, M.; Chan, A.; Vulevic, B.; Henninger, D.; Hart, K.; Sennello, R.; Li, A. H.; Zhang, T.; Richardson, F.; Emerson, D. L.; Castelhano, A. L.; Arnold, L. D.; Gibson, N. W. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models Cancer Res. 2006, 66, 1015-1024 (Pubitemid 43165969)
139. Bhide, R. S.; Cai, Z. W.; Zhang, Y. Z.; Qian, L.; Wei, D.; Barbosa, S.; Lombardo, L. J.; Borzilleri, R. M.; Zheng, X.; Wu, L. I.; Barrish, J. C.; Kim, S. H.; Leavitt, K.; Mathur, A.; Leith, L.; Chao, S.; Wautlet, B.; Mortillo, S.; Jeyaseelan, R., Sr; Kukral, D.; Hunt, J. T.; Kamath, A.; Fura, A.; Vyas, V.; Marathe, P.; D'Arienzo, C.; Derbin, G.; Fargnoli, J. Discovery and preclinical studies of (R)-1-(4-(4-fluoro-2-methyl-1 H -indol-5-yloxy)-5- methylpyrrolo[2,1- f ][1,2,4]triazin-6-yloxy)propan-2-ol (BMS-540215), an in vivo active potent VEGFR-2 inhibitor J. Med. Chem. 2006, 49, 2143-2146
140. Cai, Z. W.; Zhang, Y.; Borzilleri, R. M.; Qian, L.; Barbosa, S.; Wei, D.; Zheng, X.; Wu, L.; Fan, J.; Shi, Z.; Wautlet, B. S.; Mortillo, S.; Jeyaseelan, R., Sr.; Kukralmgrt, D. W.; Kamath, A.; Marathe, P.; D'Arienzo, C.; Derbin, G.; Barrish, J. C.; Robl, J. A.; Hunt, J. T.; Lombardo, L. J.; Fargnoli, J.; Bhide, R. S. Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1 H -indol-5-yloxy)-5-methylpyrrolo[2,1- f ][1,2,4]triazin-6-yloxy)propan-2-yl)2- aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215) J. Med. Chem. 2008, 51, 1976-1980 (Pubitemid 351438880)
141. Marathe, P. H.; Kamath, A. V.; Zhang, Y.; D'Arienzo, C.; Bhide, R.; Fargnoli, J. Preclinical pharmacokinetics and in vitro metabolism of brivanib (BMS-540215), a potent VEGFR2 inhibitor and its alanine ester prodrug brivanib alaninate Cancer Chemother. Pharmacol. 2009, 65, 55-66
142. Huynh, H.; Ngo, V. C.; Fargnoli, J.; Ayers, M.; Soo, K. C.; Koong, H. N.; Thng, C. H.; Ong, H. S.; Chung, A.; Chow, P.; Pollock, P.; Byron, S.; Tran, E. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma Clin. Cancer Res. 2008, 14, 6146-6153
143. Diaz-Padilla, I.; Siu, L. L. Brivanib alaninate for cancer Expert Opin. Invest. Drugs 2011, 20, 577-586
144. Finn, R. S.; Kang, Y. K.; Mulcahy, M.; Polite, B. N.; Lim, H. Y.; Walters, I.; Baudelet, C.; Manekas, D.; Park, J. W. Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma Clin. Cancer Res. 2012, 18, 2090-2098
145. de La Motte Rouge, T.; Galluzzi, L.; Olaussen, K. A.; Zermati, Y.; Tasdemir, E.; Robert, T.; Ripoche, H.; Lazar, V.; Dessen, P.; Harper, F.; Pierron, G.; Pinna, G.; Araujo, N.; Harel-Belan, A.; Armand, J. P.; Wong, T. W.; Soria, J. C.; Kroemer, G. A novel epidermal growth factor receptor inhibitor promotes apoptosis in non-small cell lung cancer cells resistant to erlotinib Cancer Res. 2007, 67, 6253-6262 (Pubitemid 47037507)
146. Loriot, Y.; Mordant, P.; Dorvault, N.; De la motte Rouge, T.; Bourhis, J.; Soria, J. C.; Deutsch, E. BMS-690514, a VEGFR and EGFR tyrosine kinase inhibitor, shows anti-tumoural activity on non-small-cell lung cancer xenografts and induces sequence-dependent synergistic effect with radiation Br. J. Cancer 2010, 103, 347-353
147. Wong, T. W.; Lee, F. Y.; Emanuel, S.; Fairchild, C.; Fargnoli, J.; Fink, B.; Gavai, A.; Hammell, A.; Henley, B.; Hilt, C.; Hunt, J. T.; Krishnan, B.; Kukral, D.; Lewin, A.; Malone, H.; Norris, D.; Oppenheimer, S.; Vite, G.; Yu, C. Antitumor and antiangiogenic activities of BMS-690514, an inhibitor of human EGF and VEGF receptor kinase families Clin. Cancer Res. 2011, 17, 4031-4041
148. Marathe, P.; Tang, Y.; Sleczka, B.; Rodrigues, D.; Gavai, A.; Wong, T.; Christopher, L.; Zhang, H. Preclinical pharmacokinetics and in vitro metabolism of BMS-690514, a potent inhibitor of EGFR and VEGFR2 J. Pharm. Sci. 2010, 99, 3579-3593
149. Hong, H.; Su, H.; Ma, L.; Yao, M.; Iyer, R. A.; Humphreys, W. G.; Christopher, L. J. In vitro characterization of the metabolic pathways and cytochrome P450 inhibition and induction potential of BMS-690514, an ErbB/vascular endothelial growth factor receptor inhibitor Drug Metab. Dispos. 2011, 39, 1658-1667
150. Dai, Y.; Hartandi, K.; Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bauch, J. L.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Glaser, K. B.; Harris, C. M.; Hickman, D.; Guo, J.; Li, J.; Marcotte, P. A.; Marsh, K. C.; Moskey, M. D.; Martin, R. L.; Olson, A. M.; Osterling, D. J.; Pease, L. J.; Soni, N. B.; Stewart, K. D.; Stoll, V. S.; Tapang, P.; Reuter, D. R.; Davidsen, S. K.; Michaelides, M. R. Discovery of N -(4-(3-amino-1 H -indazol-4-yl)phenyl)- N ′-(2-fluoro-5-methylphenyl)urea (ABT-869), a 3-aminoindazole-based orally active multitargeted receptor tyrosine kinase inhibitor J. Med. Chem. 2007, 50, 1584-1597 (Pubitemid 46564379)
151. Albert, D. H.; Tapang, P.; Magoc, T. J.; Pease, L. J.; Reuter, D. R.; Wie, R.; Li, J.; Guo, J.; Bousquet, P. F.; Ghoreishi-Haack, N. S.; Wang, B.; Bukofzer, G. T.; Wang, Y. C.; Stavropoulos, J. A.; Hartandi, K.; Niquette, A. L.; Soni, N.; Johnson, E. F.; McCall, J. O.; Bouska, J. J.; Luo, Y.; Donawho, C. K.; Dai, Y.; Marcotte, P. A.; Glaser, K. B.; Michaelides, M. R.; Davidsen, S. K. Preclinical activity of ABT-869, a multitargeted receptor tyrosine kinase inhibitor Mol. Cancer Ther. 2006, 5, 995-1006 (Pubitemid 43724600)
152. Jiang, F.; Albert, D. H.; Luo, Y.; Tapang, P.; Zhang, K.; Davidsen, S. K.; Fox, G. B.; Lesniewski, R.; McKeegan, E. M. ABT-869, a multitargeted receptor tyrosine kinase inhibitor, reduces tumor microvascularity and improves vascular wall integrity in preclinical tumor models J. Pharmacol. Exp. Ther. 2011, 338, 134-142
153. Luo, Y.; Jiang, F.; Cole, T. B.; Hradil, V. P.; Reuter, D.; Chakravartty, A.; Albert, D. H.; Davidsen, S. K.; Cox, B. F.; McKeegan, E. M.; Fox, G. B. A novel multi-targeted tyrosine kinase inhibitor, linifanib (ABT-869), produces functional and structural changes in tumor vasculature in an orthotopic rat glioma model Cancer Chemother. Pharmacol. 2012, 69, 911-921
154. Asahina, H.; Tamura, Y.; Nokihara, H.; Yamamoto, N.; Seki, Y.; Shibata, T.; Goto, Y.; Tanioka, M.; Yamada, Y.; Coates, A.; Chiu, Y. L.; Li, X.; Pradhan, R.; Ansell, P. J.; McKeegan, E. M.; McKee, M. D.; Carlson, D. M.; Tamura, T. An open-label, phase 1 study evaluating safety, tolerability, and pharmacokinetics of linifanib (ABT-869) in Japanese patients with solid tumors Cancer Chemother. Pharmacol. 2012, 69, 1477-1486
155. Tannir, N. M.; Wong, Y. N.; Kollmannsberger, C. K.; Ernstoff, M. S.; Perry, D. J.; Appleman, L. J.; Posadas, E. M.; Cho, D.; Choueiri, T. K.; Coates, A.; Gupta, N.; Pradhan, R.; Qian, J.; Chen, J.; Scappaticci, F. A.; Ricker, J. L.; Carlson, D. M.; Michaelson, M. D. Phase 2 trial of linifanib (ABT-869) in patients with advanced renal cell cancer after sunitinib failure Eur. J. Cancer 2011, 47, 2706-2714
156. Tan, E. H.; Goss, G. D.; Salgia, R.; Besse, B.; Gandara, D. R.; Hanna, N. H.; Yang, J. C.; Thertulien, R.; Wertheim, M.; Mazieres, J.; Hensing, T.; Lee, C.; Gupta, N.; Pradhan, R.; Qian, J.; Qin, Q.; Scappaticci, F. A.; Ricker, J. L.; Carlson, D. M.; Soo, R. A. Phase 2 trial of linifanib (ABT-869) in patients with advanced non-small cell lung cancer J. Thorac. Oncol. 2011, 6, 1418-1425
157. Traxler, P.; Allegrini, P. R.; Brandt, B.; Brueggen, J.; Cozens, R.; Fabbro, D.; Grosios, K.; Lane, H. A.; McSheehy, P.; Mestan, J.; Meyer, T.; Tang, C.; Wartmann, M.; Wood, J.; Caravatti, G. AEE788: a dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity Cancer Res. 2004, 64, 4931-4941 (Pubitemid 38924540)
158. Okamoto, K.; Neureiter, D.; Alinger, B.; Meissnitzer, M.; Sass, G.; Schmitz, V.; Di Fazio, P.; Wissniowski, T.; Gahr, S.; Hohenstein, B.; Kaufmann, B.; Schlösser, A.; Haus, U.; Hahn, E. G.; Herold, C.; Ocker, M. The dual EGF/VEGF receptor tyrosine kinase inhibitor AEE788 inhibits growth of human hepatocellular carcinoma xenografts in nude mice Int. J. Oncol. 2008, 33, 733-742
159. Meco, D.; Servidei, T.; Zannoni, G. F.; Martinelli, E.; Prisco, M. G.; de Waure, C.; Riccardi, R. Dual inhibitor AEE788 reduces tumor growth in preclinical models of medulloblastoma Transl. Oncol. 2010, 3, 326-335
160. Reardon, D. A.; Conrad, C. A.; Cloughesy, T.; Prados, M. D.; Friedman, H. S.; Aldape, K. D.; Mischel, P.; Xia, J.; Dilea, C.; Huang, J.; Mietlowski, W.; Dugan, M.; Chen, W.; Yung, W. K. Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients Cancer Chemother. Pharmacol. 2012, 69, 1507-1518
161. Iwata, H.; Imamura, S.; Hori, A.; Hixon, M. S.; Kimura, H.; Miki, H. Biochemical characterization of TAK-593, a novel VEGFR/PDGFR inhibitor with a two-step slow binding mechanism Biochemistry 2011, 50, 738-751
162. Hudkins, R. L.; Becknell, N. C.; Zulli, A. L.; Underiner, T. L.; Angeles, T. S.; Aimone, L. D.; Albom, M. S.; Chang, H.; Miknyoczki, S. J.; Hunter, K.; Jones-Bolin, S.; Zhao, H.; Bacon, E. R.; Mallamo, J. P.; Ator, M. A.; Ruggeri, B. A. Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12, 13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4 H -indazolo[5,4- a ]pyrrolo[3,4- c ]carbazol-4-one (CEP-11981): a novel oncology therapeutic agent J. Med. Chem. 2012, 55, 903-913
163. Stratmann, A.; Acker, T.; Burger, A. M.; Amann, K.; Risau, W.; Plate, K. H. Differential inhibition of tumor angiogenesis by tie2 and vascular endothelial growth factor receptor-2 dominant-negative receptor mutants Int. J. Cancer 2001, 91, 273-282 (Pubitemid 32049618)
164. Cohen, R. B.; Langer, C. J.; Simon, G. R.; Eisenberg, P. D.; Hainsworth, J. D.; Madajewicz, S.; Cosgriff, T. M.; Pierce, K.; Xu, H.; Liau, K.; Healey, D. A phase I/randomized phase II, non-comparative, multicenter, open label trial of CP-547,632 in combination with paclitaxel and carboplatin or paclitaxel and carboplatin alone as first-line treatment for advanced non-small cell lung cancer (NSCLC) Cancer Chemother. Pharmacol. 2007, 60, 81-89 (Pubitemid 46643721)
165. Scott, W.; Dumas, J.; Ladouceur, G.; Lynch, M.; Scott, W. J. Preparation of Diaryl Ureas with Kinase Inhibiting Activity. WO 2004113274, 2004.
166. Wilhelm, S. M.; Dumas, J.; Adnane, L.; Lynch, M.; Carter, C. A.; Schütz, G.; Thierauch, K. H.; Zopf, D. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity Int. J. Cancer 2011, 129, 245-255
167. Mross, K.; Frost, A.; Steinbild, S.; Hedbom, S.; Büchert, M.; Fasol, U.; Unger, C.; Krätzschmar, J.; Heinig, R.; Boix, O.; Christensen, O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors Clin. Cancer Res. 2012, 18, 2658-2667
168. Strumberg, D.; Scheulen, M. E.; Schultheis, B.; Richly, H.; Frost, A.; Büchert, M.; Christensen, O.; Jeffers, M.; Heinig, R.; Boix, O.; Mross, K. Regorafenib (BAY 73-4506) in advanced colorectal cancer: a phase I study Br. J. Cancer. 2012, 106, 1722-1727
169. Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Glivec (STI571, imatinib), a rationale developed, targeted anticancer drug Nat. Rev. Drug Discovery 2002, 1, 493-502
170. Garofalo, A.; Farce, A.; Ravez, S.; Lemoine, A.; Six, P.; Chavatte, P.; Goossens, L.; Depreux, P. Synthesis and structure-activity relationships of (aryloxy)quinazoline ureas as novel, potent, and selective vascular endothelial growth factor receptor-2 inhibitors J. Med. Chem. 2012, 55, 1189-1204
171. Zhang, S.; Cao, Z.; Tian, H.; Shen, G.; Ma, Y.; Xie, H.; Liu, Y.; Zhao, C.; Deng, S.; Yang, Y.; Zheng, R.; Li, W.; Zhang, N.; Liu, S.; Wang, W.; Dai, L.; Shi, S.; Cheng, L.; Pan, Y.; Feng, S.; Zhao, X.; Deng, H.; Yang, S.; Wei, Y. SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits angiogenesis and tumor growth in vivo Clin. Cancer Res. 2011, 17, 4439-4450
172. Shen, G.; Li, Y.; Du, T.; Shi, G.; Dai, L.; Chen, X.; Zheng, R.; Li, W.; Su, X.; Zhang, S.; Wei, Y.; Yang, S.; Deng, H. SKLB1002, a novel inhibitor of VEGF receptor 2 signaling, induces vascular normalization to improve systemically administered chemotherapy efficacy Neoplasma 2012, 59, 486-493
173. Yu, B.; Tang, L. D.; Li, Y. L.; Song, S. H.; Ji, X. L.; Lin, M. S.; Wu, C. F. Design, synthesis and antitumor activity of 4-aminoquinazoline derivatives targeting VEGFR-2 tyrosine kinase Bioorg. Med. Chem. Lett. 2012, 22, 110-114
174. Plé, P. A.; Jung, F.; Ashton, S.; Hennequin, L.; Laine, R.; Morgentin, R.; Pasquet, G.; Taylor, S. Discovery of AZD2932, a new quinazoline ether inhibitor with high affinity for VEGFR-2 and PDGFR tyrosine kinases Bioorg. Med. Chem. Lett. 2012, 22, 262-266
175. Oguro, Y.; Miyamoto, N.; Okada, K.; Takagi, T.; Iwata, H.; Awazu, Y.; Miki, H.; Hori, A.; Kamiyama, K.; Imamura, S. Design, synthesis, and evaluation of 5-methyl-4-phenoxy-5 H -pyrrolo[3,2- d ]pyrimidine derivatives: novel VEGFR2 kinase inhibitors binding to inactive kinase conformation Bioorg. Med. Chem. 2010, 18, 7260-7273
176. Oguro, Y.; Miyamoto, N.; Takagi, T.; Okada, K.; Awazu, Y.; Miki, H.; Hori, A.; Kamiyama, K.; Imamura, S. N -Phenyl- N ′-[4-(5 H -pyrrolo[3,2- d ]pyrimidin-4-yloxy)phenyl]ureas as novel inhibitors of VEGFR and FGFR kinases Bioorg. Med. Chem. 2010, 18, 7150-7163
177. Gangjee, A.; Kurup, S.; Ihnat, M. A.; Thorpe, J. E.; Shenoy, S. S. Synthesis and biological activity of N (4)-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7 H -pyrrolo[2,3- d ]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents Bioorg. Med. Chem. 2010, 18, 3575-3587
178. Frey, R. R.; Curtin, M. L.; Albert, D. H.; Glaser, K. B.; Pease, L. J.; Soni, N. B.; Bouska, J. J.; Reuter, D.; Stewart, K. D.; Marcotte, P.; Bukofzer, G.; Li, J.; Davidsen, S. K.; Michaelides, M. R. 7-Aminopyrazolo[1,5- a ]pyrimidines as potent multitargeted receptor tyrosine kinase inhibitors J. Med. Chem. 2008, 51, 3777-3787 (Pubitemid 351956509)
179. Egert-Schmidt, A. M.; Dreher, J.; Dunkel, U.; Kohfeld, S.; Preu, L.; Weber, H.; Ehlert, J. E.; Mutschler, B.; Totzke, F.; Schächtele, C.; Kubbutat, M. H.; Baumann, K.; Kunick, C. Identification of 2-anilino-9-methoxy- 5,7-dihydro-6 H -pyrimido[5,4- d ][1]benzazepin-6-ones as dual PLK1/VEGF-R2 kinase inhibitor chemotypes by structure-based lead generation J. Med. Chem. 2010, 53, 2433-2442
180. Strebhardt, K.; Ullrich, A. Targeting polo-like kinase 1 for cancer therapy Nat. Rev. Cancer 2006, 6, 321-330
181. Hughes, T. V.; Emanuel, S. L.; Beck, A. K.; Wetter, S. K.; Connolly, P. J.; Karnachi, P.; Reuman, M.; Seraj., J.; Fuentes-Pesquera, A. R.; Gruninger, R. H.; Middleton, S. A.; Lin, R.; Davis, J. M.; Moffat, D. F. 4-Aryl-5-cyano-2- aminopyrimidines as VEGF-R2 inhibitors: synthesis and biological evaluation Bioorg. Med. Chem. Lett. 2007, 17, 3266-3270 (Pubitemid 46830894)
182. Gaudette, F.; Raeppel, S.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Macleod, A. R.; Besterman, J. M.; Vaisburg, A. Identification of potent and selective VEGFR receptor tyrosine kinase inhibitors having new amide isostere headgroups Bioorg. Med. Chem. Lett. 2010, 20, 848-852
183. Huang, S.; Li, R.; LaMontagne, K. R.; Greenberger, L. M.; Connolly, P. J. 4-Aminopyrimidine-5-carbaldehyde oximes as potent VEGFR-2 inhibitors. Part II Bioorg. Med. Chem. Lett. 2011, 21, 1815-1818
184. Sakurai, K.; Yamada, N.; Yashiro, M.; Matsuzaki, T.; Komatsu, M.; Ohira, M.; Miwa, A.; Hirakawa, K. A novel angiogenesis inhibitor, Ki23057, is useful for preventing the progression of colon cancer and the spreading of cancer cells to the liver Eur. J. Cancer 2007, 43, 2612-2620 (Pubitemid 350086941)
185. Harmange, J. C.; Weiss, M. M.; Germain, J.; Polverino, A. J.; Borg, G.; Bready, J.; Chen, D.; Choquette, D.; Coxon, A.; DeMelfi, T.; DiPietro, L.; Doerr, N.; Estrada, J.; Flynn, J.; Graceffa, R. F.; Harriman, S. P.; Kaufman, S.; La, D. S.; Long, A.; Martin, M. W.; Neervannan, S.; Patel, V. F.; Potashman, M.; Regal, K.; Roveto, P. M.; Schrag, M. L.; Starnes, C.; Tasker, A.; Teffera, Y.; Wang, L.; White, R. D.; Whittington, D. A.; Zanon, R. Naphthamides as novel and potent vascular endothelial growth factor receptor tyrosine kinase inhibitors: design, synthesis, and evaluation J. Med. Chem. 2008, 51, 1649-1667 (Pubitemid 351438848)
186. Weiss, M. M.; Harmange, J. C.; Polverino, A. J.; Bauer, D.; Berry, L.; Berry, V.; Borg, G.; Bready, J.; Chen, D.; Choquette, D.; Coxon, A.; DeMelfi, T.; Doerr, N.; Estrada, J.; Flynn, J.; Graceffa, R. F.; Harriman, S. P.; Kaufman, S.; La, D. S.; Long, A.; Neervannan, S.; Patel, V. F.; Potashman, M.; Regal, K.; Roveto, P. M.; Schrag, M. L.; Starnes, C.; Tasker, A.; Teffera, Y.; Whittington, D. A.; Zanon, R. Evaluation of a series of naphthamides as potent, orally active vascular endothelial growth factor receptor-2 tyrosine kinase inhibitors J. Med. Chem. 2008, 51, 1668-1680 (Pubitemid 351438849)
187. La, D. S.; Belzile, J.; Bready, J. V.; Coxon, A.; DeMelfi, T.; Doerr, N.; Estrada, J.; Flynn, J. C.; Flynn, S. R.; Graceffa, R. F.; Harriman, S. P.; Larrow, J. F.; Long, A. M.; Martin, M. W.; Morrison, M. J.; Patel, V. F.; Roveto, P. M.; Wang, L.; Weiss, M. M.; Whittington, D. A.; Teffera, Y.; Zhao, Z.; Polverino, A. J.; Harmange, J. C. Novel 2,3-dihydro-1,4-benzoxazines as potent and orally bioavailable inhibitors of tumor-driven angiogenesis J. Med. Chem. 2008, 51, 1695-1705 (Pubitemid 351438851)
188. Bauer, D.; Whittington, D. A.; Coxon, A.; Bready, J.; Harriman, S. P.; Patel, V. F.; Polverino, A.; Harmange, J. C. Evaluation of indazole-based compounds as a new class of potent KDR/VEGFR-2 inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 4844-4848
189. Mannion, M.; Raeppel, S.; Claridge, S.; Zhou, N.; Saavedra, O.; Isakovic, L.; Zhan, L.; Gaudette, F.; Raeppel, F.; Déziel, R.; Beaulieu, N.; Nguyen, H.; Chute, I.; Beaulieu, C.; Dupont, I.; Robert, M. F.; Lefebvre, S.; Dubay, M.; Rahil, J.; Wang, J.; Ste-Croix, H.; Macleod, R. A.; Besterman, J. M.; Vaisburg, A. N -(4-(6,7-Disubstituted-quinolin-4-yloxy)-3-fluorophenyl)-2-oxo- 3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 6552-6556
190. Yang, Y.; Shi, L.; Zhou, Y.; Li, H. Q.; Zhu, Z. W.; Zhu, H. L. Design, synthesis and biological evaluation of quinoline amide derivatives as novel VEGFR-2 inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 6653-6656
191. Rizvi, S. U.; Siddiqui, H. L.; Nisar, M.; Khan, N.; Khan, I. Discovery and molecular docking of quinolyl-thienyl chalcones as anti-angiogenic agents targeting VEGFR-2 tyrosine kinase Bioorg. Med. Chem. Lett. 2012, 22, 942-944
192. Raeppel, S.; Claridge, S.; Saavedra, O.; Gaudette, F.; Zhan, L.; Mannion, M.; Zhou, N.; Raeppel, F.; Granger, M. C.; Isakovic, L.; Déziel, R.; Nguyen, H.; Beaulieu, N.; Beaulieu, C.; Dupont, I.; Robert, M. F.; Lefebvre, S.; Dubay, M.; Rahil, J.; Wang, J.; Ste-Croix, H.; Robert Macleod, A.; Besterman, J.; Vaisburg, A. N -(3-Fluoro-4-(2-arylthieno[3,2- b ]pyridin-7-yloxy)phenyl)-2- oxo-3-phenylimidazolidine-1-carboxamides: a novel series of dual c-Met/VEGFR2 receptor tyrosine kinase inhibitors Bioorg. Med. Chem. Lett. 2009, 19, 1323-1328
193. 3-Arylmalonamides: a new series of thieno[3,2- b ]pyridine based inhibitors of c-Met and VEGFR2 tyrosine kinases Bioorg. Med. Chem. Lett. 2009, 19, 6836-6839
194. Kim, K. S.; Zhang, L.; Schmidt, R.; Cai, Z. W.; Wei, D.; Williams, D. K.; Lombardo, L. J.; Trainor, G. L.; Xie, D.; Zhang, Y.; An, Y.; Sack, J. S.; Tokarski, J. S.; Darienzo, C.; Kamath, A.; Marathe, P.; Zhang, Y.; Lippy, J.; Jeyaseelan, R., Sr.; Wautlet, B.; Henley, B.; Gullo-Brown, J.; Manne, V.; Hunt, J. T.; Fargnoli, J.; Borzilleri, R. M. Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities J. Med. Chem. 2008, 51, 5330-5341
195. Dai, Y.; Hartandi, K.; Soni, N. B.; Pease, L. J.; Reuter, D. R.; Olson, A. M.; Osterling, D. J.; Doktor, S. Z.; Albert, D. H.; Bouska, J. J.; Glaser, K. B.; Marcotte, P. A.; Stewart, K. D.; Davidsen, S. K.; Michaelides, M. R. Identification of aminopyrazolopyridine ureas as potent VEGFR/PDGFR multitargeted kinase inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 386-390
196. Kiselyov, A. S.; Semenova, M.; Semenov, V. V. 3,4-Disubstituted isothiazoles: novel potent inhibitors of VEGF receptors 1 and 2 Bioorg. Med. Chem. Lett. 2009, 19, 1195-1198
197. Kiselyov, A. S.; Semenova, M.; Semenov, V. V. (1,2,3-Triazol-4-yl) benzenamines: synthesis and activity against VEGF receptors 1 and 2 Bioorg. Med. Chem. Lett. 2009, 19, 1344-1348
198. Choi, H. E.; Yoo, M. S.; Choi, J. H.; Lee, J. Y.; Kim, J. H.; Kim, J. H.; Lee, J. K.; Kim, G. I.; Park, Y.; Chi, Y. H.; Paik, S. H.; Lee, J. H.; Lee, K. T. BRN-103, a novel nicotinamide derivative, inhibits VEGF-induced angiogenesis and proliferation in human umbilical vein endothelial cells Bioorg. Med. Chem. Lett. 2011, 21, 6236-6241
199. Cao, Z. X.; Zheng, R. L.; Lin, H. J.; Luo, S. D.; Zhou, Y.; Xu, Y. Z.; Zeng, X. X.; Wang, Z.; Zhou, L. N.; Mao, Y. Q.; Yang, L.; Wei, Y. Q.; Yu, L. T.; Yang, S. Y.; Zhao, Y. L. SKLB610: a novel potential inhibitor of vascular endothelial growth factor receptor tyrosine kinases inhibits angiogenesis and tumor growth in vivo Cell. Physiol. Biochem. 2011, 27, 565-574
200. Dandu, R.; Zulli, A. L.; Bacon, E. R.; Underiner, T.; Robinson, C.; Chang, H.; Miknyoczki, S.; Grobelny, J.; Ruggeri, B. A.; Yang, S.; Albom, M. S.; Angeles, T. S.; Aimone, L. D.; Hudkins, R. L. Design and synthesis of dihydroindazolo[5,4- a ]pyrrolo[3,4- c ]carbazole oximes as potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases Bioorg. Med. Chem. Lett. 2008, 18, 1916-1921 (Pubitemid 351380896)
201. Underiner, T. L.; Ruggeri, B.; Aimone, L.; Albom, M.; Angeles, T.; Chang, H.; Hudkins, R. L.; Hunter, K.; Josef, K.; Robinson, C.; Weinberg, L.; Yang, S.; Zulli, A. TIE-2/VEGF-R2 SAR and in vitro activity of C3-acyl dihydroindazolo[5,4- a ]pyrrolo[3,4- c ]carbazole analogs Bioorg. Med. Chem. Lett. 2008, 18, 2368-2372 (Pubitemid 351442900)
202. Hudkins, R. L.; Zulli, A. L.; Underiner, T. L.; Angeles, T. S.; Aimone, L. D.; Meyer, S. L.; Pauletti, D.; Chang, H.; Fedorov, E. V.; Almo, S. C.; Fedorov, A. A.; Ruggeri, B. A. 8-THP-DHI analogs as potent type I dual TIE-2/VEGF-R2 receptor tyrosine kinase inhibitors Bioorg. Med. Chem. Lett. 2010, 20, 3356-3360
203. Peifer, C.; Selig, R.; Kinkel, K.; Ott, D.; Totzke, F.; Schächtele, C.; Heidenreich, R.; Röcken, M.; Schollmeyer, D.; Laufer, S. Design, synthesis, and biological evaluation of novel 3-aryl-4-(1 H -indole-3yl)-1,5- dihydro-2 H -pyrrole-2-ones as vascular endothelial growth factor receptor (VEGF-R) inhibitors J. Med. Chem. 2008, 51, 3814-3824 (Pubitemid 351956512)
204. Cho, T. P.; Dong, S. Y.; Jun, F.; Hong, F. J.; Liang, Y. J.; Lu, X.; Hua, P. J.; Li, L. Y.; Lei, Z.; Bing, H.; Ying, Z.; Qiong, L. F.; Bei, F. B.; Guang, L. L.; Shen, G. A.; Hong, S. G.; Hong, S. W.; Tai, M. X. Novel potent orally active multitargeted receptor tyrosine kinase inhibitors: synthesis, structure-activity relationships, and antitumor activities of 2-indolinone derivatives J. Med. Chem. 2010, 53, 8140-8149
205. Wang, D.; Tang, F.; Wang, S.; Jiang, Z.; Zhang, L. Preclinical anti-angiogenesis and anti-tumor activity of SIM010603, an oral, multi-targets receptor tyrosine kinases inhibitor Cancer Chemother. Pharmacol. 2012, 69, 173-183
206. Cai, Z. W.; Wei, D.; Borzilleri, R. M.; Qian, L.; Kamath, A.; Mortillo, S.; Wautlet, B.; Henley, B. J.; Jeyaseelan, R., Sr.; Tokarski, J.; Hunt, J. T.; Bhide, R. S.; Fargnoli, J.; Lombardo, L. J. Synthesis, SAR, and evaluation of 4-[2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino]pyrrolo[2,1- f ][1,2,4]triazine-based VEGFR-2 kinase inhibitors Bioorg. Med. Chem. Lett. 2008, 18, 1354-1358 (Pubitemid 351226537)
207. Ruel, R.; Thibeault, C.; L'Heureux, A.; Martel, A.; Cai, Z. W.; Wei, D.; Qian, L.; Barrish, J. C.; Mathur, A.; D'Arienzo, C.; Hunt, J. T.; Kamath, A.; Marathe, P.; Zhang, Y.; Derbin, G.; Wautlet, B.; Mortillo, S.; Jeyaseelan, R., Sr; Henley, B.; Tejwani, R.; Bhide, R. S.; Trainor, G. L.; Fargnoli, J.; Lombardo, L. J. Discovery and preclinical studies of 5-isopropyl-6-(5-methyl-1, 3,4-oxadiazol-2-yl)- N -(2-methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (BMS-645737), an in vivo active potent VEGFR-2 inhibitor Bioorg. Med. Chem. Lett. 2008, 18, 2985-2989 (Pubitemid 351608864)
208. Ji, Z.; Ahmed, A. A.; Albert, D. H.; Bouska, J. J.; Bousquet, P. F.; Cunha, G. A.; Diaz, G.; Glaser, K. B.; Guo, J.; Harris, C. M.; Li, J.; Marcotte, P. A.; Moskey, M. D.; Oie, T.; Pease, L.; Soni, N. B.; Stewart, K. D.; Davidsen, S. K.; Michaelides, M. R. 3-Amino-benzo[ d ]isoxazoles as novel multitargeted inhibitors of receptor tyrosine kinases J. Med. Chem. 2008, 51, 1231-1241 (Pubitemid 351480385)
209. Abu Thaher, B.; Arnsmann, M.; Totzke, F.; Ehlert, J. E.; Kubbutat, M. H.; Schächtele, C.; Zimmermann, M. O.; Koch, P.; Boeckler, F. M.; Laufer, S. A. Tri- and tetrasubstituted pyrazole derivates: regioisomerism switches activity from p38MAP kinase to important cancer kinases J. Med. Chem. 2012, 55, 961-965
210. Bologna, M.; Vicentini, C.; Muzi, P.; Pace, G.; Angelucci, A. Cancer multitarget pharmacology in prostate tumors: tyrosine kinase inhibitors and beyond Curr. Med. Chem. 2011, 18, 2827-2835
211. Apsel, B.; Blair, J. A.; Gonzalez, B.; Nazif, T. M.; Feldman, M. E.; Aizenstein, B.; Hoffman, R.; Williams, R. L.; Shokat, K. M.; Knight, Z. A. Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases Nat. Chem. Biol. 2008, 4, 691-699