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Chemical Compound Review

Orantinib     3-[2,4-dimethyl-5-[(Z)-(2- oxo-1H-indol-3...

Synonyms: TSU-68, TSU68, PubChem22441, S1470_Selleck, CHEMBL274654, ...
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Disease relevance of SU6668


High impact information on SU6668

  • In contrast, a kinase inhibitor incorporating selectivity for PDGFRs (SU6668) is shown to block further growth of end-stage tumors, eliciting detachment of pericytes and disruption of tumor vascularity [6].
  • In patient blasts, both SU5416 and SU6668 inhibited SCF-induced phosphorylation of c-kit and ERK1/2 and induced apoptosis [1].
  • Tyrosine autophosphorylation of the receptor, induced by SCF, was inhibited in these cells by SU5416 and SU6668 in a dose-dependent manner (inhibitory concentration of 50% [IC(50)] 0.1-1 microM) [1].
  • Substitution of SU5416 with any one of ZD6474, SU6668, IMC-1121, a monoclonal antibody to VEGFR-2, or an antibody to VEGF (bevacizumab) did not cause a marked increase in the coagulation index, nor did the combination of SU5416 with 5-fluorouracil and leucovorin [7].
  • By employing immobilized SU6668 for the affinity capture of cellular drug targets in combination with mass spectrometry, we identified previously unknown targets of SU6668 including Aurora kinases and TANK-binding kinase 1 [8].

Chemical compound and disease context of SU6668


Biological context of SU6668

  • SU6668 increased median survival by 58% (P < 0.001) and led to a progressive increase in tumor cell and endothelial cell apoptosis that increased over time [5].
  • SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro [11].
  • SU5416 and SU6668 respectively inhibited metastases (48.1% and 55.3%), microvessel formation (42.0% and 36.2%), and cell proliferation (24.4% and 27.3%) and increased tumor cell (by 2.6- and 4.3-fold) and endothelial cell (by 18.6- and 81.4-fold) apoptosis (P<0.001) [12].
  • In a parallel experiment, groups of mice were sacrificed at earlier time points to better define the kinetics of the effect of SU6668 on angiogenic parameters over time [5].
  • Using rational drug design coupled with traditional screening technologies, we have discovered SU6668, a novel inhibitor of these receptors [4].

Anatomical context of SU6668


Associations of SU6668 with other chemical compounds


Gene context of SU6668

  • Biochemical kinetic studies using isolated Flk-1, FGF receptor 1, and PDGF receptor beta kinases revealed that SU6668 has competitive inhibitory properties with respect to ATP [4].
  • At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours [20].
  • These results suggest that inhibition of Vegf, Fgf and Pdgf receptor function by SU5416 and SU6668 can enhance the efficacy of irradiation [21].
  • Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly ( approximately 50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis [20].
  • To test this hypothesis, we used the small molecule inhibitors SU5416 (an inhibitor for Vegf receptor) and SU6668 (an inhibitor for Vegf, Fgf and Pdgf receptors) alone and in combination with fractionated irradiation to treat C3H mice bearing SCC VII carcinomas [21].

Analytical, diagnostic and therapeutic context of SU6668


  1. The antiangiogenic protein kinase inhibitors SU5416 and SU6668 inhibit the SCF receptor (c-kit) in a human myeloid leukemia cell line and in acute myeloid leukemia blasts. Smolich, B.D., Yuen, H.A., West, K.A., Giles, F.J., Albitar, M., Cherrington, J.M. Blood (2001) [Pubmed]
  2. In vivo intracellular signaling as a marker of antiangiogenic activity. Solorzano, C.C., Jung, Y.D., Bucana, C.D., McConkey, D.J., Gallick, G.E., McMahon, G., Ellis, L.M. Cancer Res. (2001) [Pubmed]
  3. Combined therapy of local and metastatic 4T1 breast tumor in mice using SU6668, an inhibitor of angiogenic receptor tyrosine kinases, and the immunostimulator B7.2-IgG fusion protein. Huang, X., Wong, M.K., Yi, H., Watkins, S., Laird, A.D., Wolf, S.F., Gorelik, E. Cancer Res. (2002) [Pubmed]
  4. SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Laird, A.D., Vajkoczy, P., Shawver, L.K., Thurnher, A., Liang, C., Mohammadi, M., Schlessinger, J., Ullrich, A., Hubbard, S.R., Blake, R.A., Fong, T.A., Strawn, L.M., Sun, L., Tang, C., Hawtin, R., Tang, F., Shenoy, N., Hirth, K.P., McMahon, G., Cherrington, n.u.l.l. Cancer Res. (2000) [Pubmed]
  5. Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms. Shaheen, R.M., Tseng, W.W., Davis, D.W., Liu, W., Reinmuth, N., Vellagas, R., Wieczorek, A.A., Ogura, Y., McConkey, D.J., Drazan, K.E., Bucana, C.D., McMahon, G., Ellis, L.M. Cancer Res. (2001) [Pubmed]
  6. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E., Hanahan, D. J. Clin. Invest. (2003) [Pubmed]
  7. In vitro procoagulant activity induced in endothelial cells by chemotherapy and antiangiogenic drug combinations: modulation by lower-dose chemotherapy. Ma, L., Francia, G., Viloria-Petit, A., Hicklin, D.J., du Manoir, J., Rak, J., Kerbel, R.S. Cancer Res. (2005) [Pubmed]
  8. Proteomic characterization of the angiogenesis inhibitor SU6668 reveals multiple impacts on cellular kinase signaling. Godl, K., Gruss, O.J., Eickhoff, J., Wissing, J., Blencke, S., Weber, M., Degen, H., Brehmer, D., Orfi, L., Horváth, Z., Kéri, G., Müller, S., Cotten, M., Ullrich, A., Daub, H. Cancer Res. (2005) [Pubmed]
  9. Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU-68). Machida, S., Saga, Y., Takei, Y., Mizuno, I., Takayama, T., Kohno, T., Konno, R., Ohwada, M., Suzuki, M. Int. J. Cancer (2005) [Pubmed]
  10. Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo. Klenke, F.M., Abdollahi, A., Bertl, E., Gebhard, M.M., Ewerbeck, V., Huber, P.E., Sckell, A. BMC Cancer (2007) [Pubmed]
  11. SU5416 and SU6668 attenuate the angiogenic effects of radiation-induced tumor cell growth factor production and amplify the direct anti-endothelial action of radiation in vitro. Abdollahi, A., Lipson, K.E., Han, X., Krempien, R., Trinh, T., Weber, K.J., Hahnfeldt, P., Hlatky, L., Debus, J., Howlett, A.R., Huber, P.E. Cancer Res. (2003) [Pubmed]
  12. Antiangiogenic therapy targeting the tyrosine kinase receptor for vascular endothelial growth factor receptor inhibits the growth of colon cancer liver metastasis and induces tumor and endothelial cell apoptosis. Shaheen, R.M., Davis, D.W., Liu, W., Zebrowski, B.K., Wilson, M.R., Bucana, C.D., McConkey, D.J., McMahon, G., Ellis, L.M. Cancer Res. (1999) [Pubmed]
  13. Simultaneous inhibition of the receptor kinase activity of vascular endothelial, fibroblast, and platelet-derived growth factors suppresses tumor growth and enhances tumor radiation response. Griffin, R.J., Williams, B.W., Wild, R., Cherrington, J.M., Park, H., Song, C.W. Cancer Res. (2002) [Pubmed]
  14. Down-modulation of monocyte transendothelial migration and endothelial adhesion molecule expression by fibroblast growth factor: reversal by the anti-angiogenic agent SU6668. Zhang, H., Issekutz, A.C. Am. J. Pathol. (2002) [Pubmed]
  15. The combination of the tyrosine kinase receptor inhibitor SU6668 with paclitaxel affects ascites formation and tumor spread in ovarian carcinoma xenografts growing orthotopically. Garofalo, A., Naumova, E., Manenti, L., Ghilardi, C., Ghisleni, G., Caniatti, M., Colombo, T., Cherrington, J.M., Scanziani, E., Nicoletti, M.I., Giavazzi, R. Clin. Cancer Res. (2003) [Pubmed]
  16. Dose-finding study of the multitargeted tyrosine kinase inhibitor SU6668 in patients with advanced malignancies. Kuenen, B.C., Giaccone, G., Ruijter, R., Kok, A., Schalkwijk, C., Hoekman, K., Pinedo, H.M. Clin. Cancer Res. (2005) [Pubmed]
  17. An Orally Administered Multitarget Tyrosine Kinase Inhibitor, SU11248, Is a Novel Potent Inhibitor of Thyroid Oncogenic RET/Papillary Thyroid Cancer Kinases. Kim, D.W., Jo, Y.S., Jung, H.S., Chung, H.K., Song, J.H., Park, K.C., Park, S.H., Hwang, J.H., Rha, S.Y., Kweon, G.R., Lee, S.J., Jo, K.W., Shong, M. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  18. A multitargeted receptor tyrosine kinase inhibitor, SU6668, does not affect the healing of cutaneous full-thickness incisional wounds in SKH-1 mice. Duan, W.R., Patyna, S., Kuhlmann, M.A., Li, S., Blomme, E.A. Journal of investigative surgery : the official journal of the Academy of Surgical Research. (2006) [Pubmed]
  19. Comparative study of isoflavone, quinoxaline and oxindole families of anti-angiogenic agents. Whatmore, J.L., Swann, E., Barraja, P., Newsome, J.J., Bunderson, M., Beall, H.D., Tooke, J.E., Moody, C.J. Angiogenesis (2002) [Pubmed]
  20. Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668. Davis, D.W., Takamori, R., Raut, C.P., Xiong, H.Q., Herbst, R.S., Stadler, W.M., Heymach, J.V., Demetri, G.D., Rashid, A., Shen, Y., Wen, S., Abbruzzese, J.L., McConkey, D.J. Clin. Cancer Res. (2005) [Pubmed]
  21. The antiangiogenic agents SU5416 and SU6668 increase the antitumor effects of fractionated irradiation. Ning, S., Laird, D., Cherrington, J.M., Knox, S.J. Radiat. Res. (2002) [Pubmed]
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