Disease relevance of SU6668

• The c-kit kinase inhibitory activity of SU5416 and SU6668 was evaluated in MO7E cells, a human myeloid leukemia cell line [1].
• We determined the effect of an antiangiogenic tyrosine kinase inhibitor, SU6668, on tumor EC signaling in liver metastases in mice [2].
• The therapeutic efficacy of combined antiangiogenic and immune therapy was tested against weakly immunogenic and highly metastatic 4T1 breast tumor using SU6668, an angiogenesis inhibitor and recombinant murine (rm) B7.2-IgG fusion protein, an immunostimulator [3].
• Oral or i.p. administration of SU6668 in athymic mice resulted in significant growth inhibition of a diverse panel of human tumor xenografts of glioma, melanoma, lung, colon, ovarian, and epidermoid origin [4].
• BALB/c mice underwent splenic injection with CT-26 colon cancer cells to generate liver metastases and received administration of either vehicle alone or a tyrosine kinase inhibitor for vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor receptors (SU6668) [5].

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

• Inhibition of peritoneal dissemination of ovarian cancer by tyrosine kinase receptor inhibitor SU6668 (TSU-68) [9].
• From day 7 after tumor implantation, five animals were treated with SU6668 (250 mg/kg body weight, s.c.) at intervals of 48 hours (SU6668), and five animals with the equivalent amount of the CMC-based vehicle (Control) [10].

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

• On the contrary, tumors in mice immunized with B7.2-IgG/TC and treated with SU6668 had higher numbers of tumor infiltrating T cells than tumors of other groups [3].
• Our results suggest that SU6668 increased the radiosensitivity of tumor blood vessels [13].
• Down-modulation of monocyte transendothelial migration and endothelial adhesion molecule expression by fibroblast growth factor: reversal by the anti-angiogenic agent SU6668 [14].
• CONCLUSIONS: This study shows that SU6668 in combination with paclitaxel inhibits ovarian carcinoma progression in the peritoneal cavity, by blocking ascites formation and tumor spread [15].
• PURPOSE: SU6668 is a tyrosine kinase inhibitor which targets platelet-derived growth factor receptor-beta, fibroblast growth factor receptor-1, vascular endothelial growth factor receptor-2, and KIT [16].

Associations of SU6668 with other chemical compounds

• Both compounds also inhibited SCF-induced proliferation of MO7E cells (IC(50) 0.1 microM for SU5416; 0.29 microM for SU6668) [1].
• Results: An in vitro kinase assay revealed that SU5416, SU6668, and SU11248 inhibited phosphorylation of the synthetic tyrosine kinase substrate peptide E4Y by RET/PTC3 in a dose-dependent manner with IC(50) of approximately 944 nm for SU5416, 562 nm for SU6668, and 224 nm for SU11248 [17].
• Mice were administered vehicle, SU6668 (100 or 400 mg/kg/day, b.i.d.), or dexamethasone (1 mg/kg/day, b.i.d.), and wound healing was monitored histologically and using a tensiometer [18].
• The results indicate that the SU compounds, SU1433, SU 5416 and SU6668, are more potent inhibitors of VEGF-induced angiogenesis than indomethacin or the naturally occurring biochanin A, presumably because they inhibit VEGF receptor signalling [19].

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

• Finally, SU6668 treatment induced striking regression of large established human tumor xenografts [4].
• We conclude that SU6668 is a potent therapeutic agent potentially useful to suppress tumor growth and enhance the response of tumors to radiotherapy [13].
• There was little or no change in normal tissue blood perfusion, whereas in SCK tumors the perfusion decreased by 50% at 1 h after a single i.p. injection of SU6668, slightly recovered at 4 h, and completely recovered by 8 h [13].
• Investigations of SU6668 activity in cancer patients are ongoing in Phase I clinical trials [4].
• In a coculture system of PC3 prostate cancer cells and endothelial cells, isolated irradiation of the PC3 cells enhanced endothelial cell invasiveness through a Matrigel matrix, which was inhibited by SU5416 and SU6668 [11].

References