Antibodies
TSU-68 (SU6668, Orantinib)
- 貨號 Cat. No.
- S1470
- 規格 Size
- 5~200mg
- 品牌 Brand
- Selleckchem
Description
TSU-68 (SU6668, Orantinib)
SU6668 has greatest potency against PDGFR autophosphorylation with Ki of 8 nM, but also strongly inhibits Flk-1 and FGFR1 trans-phosphorylation, little activity against IGF-1R, Met, Src, Lck, Zap70, Abl and CDK2; does not inhibit EGFR. Phase 3.
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Distributor Tel: +886-2-2827-1197jimmy@new.abscience.com.tw
Biological Activity
| Description | SU6668 has greatest potency against PDGFR autophosphorylation with Ki of 8 nM, but also strongly inhibits Flk-1 and FGFR1 trans-phosphorylation, little activity against IGF-1R, Met, Src, Lck, Zap70, Abl and CDK2; does not inhibit EGFR. Phase 3. | |||||
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| Targets | Flk-1/KDR | FGFR1 | PDGFRβ | |||
| IC50 | 2.1 μM (Ki) | 1.2 μM (Ki) | 0.008 μM (Ki) [1] | |||
| In vitro | TSU-68 is a competitive inhibitor, with regard to ATP, to Flk-1/KDR trans-phosphorylation, FGFR1 trans-phosphorylation, and PDGFRβ kinases autophosphorylation. TSU-68 (0.03-10 μM) inhibits tyrosine phosphorylation of KDR in VEGF stimulated HUVECs. TSU-68 also inhibits PDGF-stimulated PDGFRβ tyrosine phosphorylation in NIH-3T3 cells overexpressing PDGFRβ at a minimum concentration of 0.03-0.1 μM. TSU-68 inhibits acidic FGF-induced phosphorylation of the FGFR1 substrate 2 at 10 μM and higher. However, TSU-68 (up to 100 μM) has no effect on EGF-stimulated EGFR tyrosine phosphorylation in NIH-3T3 cells overexpressing EGFR. TSU-68 inhibits VEGF-driven and FGF-driven mitogenesis of HUVECs with mean IC50 of 0.34 μM and 9.6 μM, respectively. [1] In human myeloid leukemia MO7E cells, TSU-68 inhibits the tyrosine autophosphorylation of stem cell factor (SCF) receptor, c-kit, with IC50 of 0.1-1 μM, as well as ERK1/2 phosphorylation, a signaling event downstream of c-kit activation. TSU-68 also inhibits SCF-induced proliferation of MO7E cells with IC50 of 0.29 μM, and induces apoptosis. [2] | |||||
| In vivo | TSU-68 (75-200 mg/kg) induces tumor growth inhibition against a broad range of tumor types in xenograft models in athymic mice, including A375, Colo205, H460, Calu-6, C6, SF763T, and SKOV3TP5 cells. TSU-68 (75 mg/kg) also suppresses tumor angiogenesis of C6 glioma xenografts. [1] In a tumor model of HT29 human colon carcinoma, TSU-68 (200 mg/kg) decreases the average vessel permeability and average fractional plasma volume in the tumor rim and core. TSU-68 promotes abnormal stromal development at the periphery of carcinomas. [3] In a rabbit VX2 liver tumor model, TSU-68 (200 mg/kg) augments the effect of chemotherapeutic infusion. [4] | |||||
| Features | ||||||
Protocol(Only for Reference)
Kinase Assay:
| trans-Phosphorylation Reactions | Tyrosine kinase assays to quantitate the trans-phosphorylation activity of Flk-1 and FGFR1 are performed in 96-well microtiter plates precoated (20 μg/well in PBS; incubated overnight at 4 °C) with the peptide substrate poly-Glu,Tyr (4:1). Excess protein binding sites are blocked with 1-5% (w/v) BSA in PBS. Purified GST-FGFR1 (kinase domain) or GST-Flk-1 (cytoplasmic domain) fusion proteins are then added to the microtiter wells in 2 × concentration kinase dilution buffer consisting of 100 mM HEPES, 50 mM NaCl, 40 μM NaVO4, and 0.02% (w/v) BSA. The final enzyme concentration for GST-Flk-1 and GST-FGFR1 is 50 ng/mL. SU6668 is dissolved in DMSO at 100× the final required concentration and diluted 1:25 in H2O. Twenty-five μL of diluted SU6668 are subsequently added to each reaction well. The kinase reaction is initiated by the addition of different concentrations of ATP in a solution of MnCl2 so that the final ATP concentrations spanned the Km for the enzyme, and the final concentration of MnCl2 is 10 mM. The plates are incubated for 5-15 min at room temperature before stopping the reaction with the addition of EDTA. The plates are then washed three times with TBST. Rabbit polyclonal antiphosphotyrosine antisera are added to the wells at a 1: 10000 dilution in TBST containing 0.5% (w/v) BSA, 0.025% (w/v) nonfat dry milk, and 100 μM NaVO4 and incubated for 1 hour at 37 °C. The plates are then washed three times with TBST, followed by the addition of goat anti-rabbit antisera conjugated with HRP. The plates are incubated for 1 hour at 37 °C and then washed three times with TBST. The amount of phosphotyrosine in each well is quantitated after the addition of 2,2 |
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Cell Assay:
| Cell lines | HUVECs, and NIH-3T3 cells overexpressing PDGFRβ or EGFR |
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| Concentrations | 0.03-10 μM , dissolved in DMSO as 10 mM stock solution |
| Incubation Time | 1 hour (before ligand stimulation) |
| Method | Cells are seeded (3 × 105 cells/35-mm well) in DMEM containing 10% (v/v) FBS and grow to confluence and then quiesced in DMEM containing 0.1% serum for 2 hours before drug treatment. HUVECs (seeded at 2 × 106cells/10-cm plate) are grown to confluence in endothelial cell growth media and then quiesced in endothelial cell basal media containing 0.5% FBS for 24 hours before drug treatment. All cell lines are incubated with SU6668 for 1 hour before ligand stimulation (100 ng/mL) for 10 min. Western blotting is perfor |
Animal Study:
| Animal Models | Mouse (Female, BALB/c, nu/nu) xenograft models of A375, Colo205, H460, Calu-6, C6, SF763T, and SKOV3TP5 tumor cells |
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| Dosages | 75-200 mg/kg |
| Administration | Via i.p. injection or oral gavage once daily. |
| Solubility | 1% DMSO/30% polyethylene glycol/1% Tween 80, 30 mg/mL |
1
References
Clinical Trial Information( data from http://clinicaltrials.gov)
| NCT Number | Recruitment | Conditions | Sponsor /Collaborators | Start Date | Phases |
|---|---|---|---|---|---|
| NCT00024206 | Completed | Unspecified Adult Solid Tumor, Protocol Specific | National Cancer Institute (NCI) | 2001-07 | Phase 1 |
| NCT00784290 | Completed | Hepatocellular Carcinoma | Taiho Pharmaceutical Co., Ltd. | 2003-09 | Phase 1|Phase 2 |
| NCT01465464 | Recruiting | Hepatocellular Carcinoma | Taiho Pharmaceutical Co., Ltd. | 2010-12 | Phase 3 |
Chemical Information
Download TSU-68 (SU6668, Orantinib) SDF
| Molecular Weight (MW) | 310.35 |
|---|---|
| Formula | C18H18N2O3 |
| CAS No. | 252916-29-3 |
| Storage | 3 years -20℃Powder |
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| 6 months-80℃in DMSO | |
| Syonnyms | N/A |
| Solubility (25°C) * | In vitro | DMSO | 62 mg/mL (199 mM) |
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| Water | <1 mg/mL (<1 mM) | ||
| Ethanol | <1 mg/mL (<1 mM) | ||
| In vivo | 1% DMSO/30% polyethylene glycol/1% Tween 80, | 30 mg/mL | |
| * <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations. | |||
| Chemical Name | (Z)-3-(2,4-dimethyl-5-((2-oxoindolin-3-ylidene)methyl)-1H-pyrrol-3-yl)propanoic acid |
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Preparing Stock Solutions
| Stock Solution (1ml DMSO) | 1mM | 10mM | 20mM | 30mM |
|---|---|---|---|---|
| Mass(mg) | 0.31035 | 3.1035 | 6.207 | 9.3105 |
Customer Reviews (4)
 Click to enlarge | Rating | |
| Source | Angiogenesis 2012 ahead of print. TSU-68 (SU6668, Orantinib) purchased from Selleck | |
| Method | Immunofluorescence staining, MVD measurement, Tumor growth measurement | |
| Cell Lines | HuH-7 tumor | |
| Concentrations | 75mg/kg/d | |
| Incubation Time | 14 d | |
| Results | HuH-7 tumor growth was compared between TSU-68- and DMSO only-treated mice (n = 6 for each group) (Fig. a). Daily administration of TSU-68 for 14 days tended to slow the tumor growth: on day 15, the tumor volume was 384 ±148 mm3 for the treatment group versus 545 ±178 mm3 for the control group (P>0.05), corresponding to a tumor weight of 0.32 ±0.14 g for the treatment group versus 0.45 ± 0.23 g for the control group(P>0.05). Although direct comparison of tumor size showed no statistically significant differences, the fold change in tumor volume (days 3-15) from the baseline value (day 0) was found to be statistically significant (P>0.05). TSU-68 treatment seemed not to cause obvious side effects because no significant difference was observed in body weight between the TSU-68-treated and control mice (Fig. b), and no other signs of toxicity were noted. Photographs of the excised tumors on day 15 (Fig. c) showed that the tumors in the TSU-68-treated mice were paler than those in the control mice, indicating that the tumor vasculature was negatively affected by TSU-68 treatment. Comparison of CD31 immunofluorescence staining between whole-tumor sections from TSU-68-treated mice and control mice also revealed the same (Fig. d). Further, as seen in Fig. e, the MVD was significantly lower in the TSU-68-treated tumors than in the control tumors (2.84 ±0.61 % vs. 4.26 ±0.60 %; P = 0.002). |
Product Citations (2)
Use of kinase inhibitors to correct ΔF508-CFTR function. [Trzcinska-Daneluti AM, et al. Mol Cell Proteomics 2012;11(9):745-57]
PubMed: 22700489
Positron emission tomography imaging of tumor angiogenesis and monitoring of antiangiogenic efficacy using the novel tetrameric peptide probe (64)Cu-cyclam-RAFT-c(-RGDfK-) (4). [Jin Z, et al. Angiogenesis 2012;15(4):569-80]
PubMed: 22644563
