TSU-68 (SU6668, Orantinib)

Catalog No.S1470 Synonyms: NSC 702827

TSU-68 (SU6668, Orantinib) Chemical Structure

Molecular Weight(MW): 310.35

TSU-68 (SU6668, Orantinib) has greatest potency against PDGFR autophosphorylation with Ki of 8 nM in a cell-free assay, 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.

Size Price Stock Quantity  
In DMSO USD 90 In stock
USD 70 In stock
USD 120 In stock
USD 470 In stock

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4 Customer Reviews

  • Effect of select kinase inhibitors on DF508-CFTR maturation analyzed by immunoblotting. 293MSR-GT cells stably expressing DF508-CFTR were treated with 15 uM kinase inhibitors or 0.3% DMSO (vehicle control), as indicated, grown at 37°C for 48 h, and the appearance of the mature protein, band C, monitored by immunoblotting with anti-CFTR antibodies. Band B represents the immature protein. DMSO represents vehicle- alone control, 27°C represents temperature rescue of F508-CFTR at 27°C, 37°C represents untreated DF508-CFTR control, and WT represents WT-CFTR. Top panels depict the anti-CFTR immunoblot and bottom panels depict actin (loading) control. ** represents cellular toxicity.

    Mol Cell Proteomics 2012 TSU-68 (SU6668, Orantinib) purchased from Selleck.

    Effect of kinase inhibitors on cell surface expression of DF508-CFTR analyzed by flow cytometry. Summary of increase in cell surface expression of DF508-CFTR (% change in fluorescence intensity) of the hits analyzed by flow cytometry (two independent experiments, 10,000 live cells per treatment per experiment).

    Mol Cell Proteomics 2012 TSU-68 (SU6668, Orantinib) purchased from Selleck.

  • (A) Tumor growth curve of s.c. HuH-7 tumor-bearing mice treated with daily i.p. injections of TSU-68 (75 mg/kg/d in 50 μl of DMSO) or the vehicle alone(50 μl of DMSO). Data are presented as the mean ±SD of tumor volumes. Day 0: the day before treatment; days 1-14: treatment days; day 15: 1 day after treatment. (B) Changes in the body weight of TSU-68- and vehicle-treated mice. (C) Image of TSU-68- and vehicle-treated tumors excised on day 15. (D) Representative immunofluorescence staining of tumor sections from TSU-68-and vehicle-treated tumors using anti-mouse CD31 antibody (green). Scale bar = 1,000 μm. (E) The tumor MVD presented as the percentage of the CD31-positive area was compared between tumors from TSU-68- and vehicle-treated mice. All data presented in (A-E) are from the same set of experimental groups (n = 6 for each group).

    Angiogenesis 2012 15, 569-80. TSU-68 (SU6668, Orantinib) purchased from Selleck.

    Transverse and coronal PET images of s.c. HuH-7 tumor-bearing mice at 3 h after i.v. injection of 64Cu-cyclam-RAFT-c(-RGDfK-)4 (11.1 MBq) on the day after daily i.p. injections of (a) vehicle alone (50 μl of DMSO) or (b) TSU-68 (75 mg/kg/d in 50 μl of DMSO) for 14 days (n = 4 mice for each group). The arrows indicate the tumor location. Representative autoradiographic examination (c, e) and CD31 immunofluorescence staining (d, f) with the same whole-tumor sections from (c, d) vehicle- and (e, f) TSU-68-treated tumors excised after PET imaging. g MVD, ha` SUVmean , and hb`SUVmax were compared between TSU-68- and vehicle-treated tumors. All data presented in a-h are from the same set of experimental groups.

    Angiogenesis 2012 15, 569-80. TSU-68 (SU6668, Orantinib) purchased from Selleck.

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Notes:

2. For more details, such as half maximal inhibitory concentrations (IC50s) and working concentrations of each inhibitor, please click on the link of the inhibitor of interest.
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Biological Activity

Description TSU-68 (SU6668, Orantinib) has greatest potency against PDGFR autophosphorylation with Ki of 8 nM in a cell-free assay, 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.
Targets
PDGFRβ [1]
(Cell-free assay)
FGFR1 [1]
(Cell-free assay)
Flk1 [1]
(Cell-free assay)
8 nM(Ki) 1.2 μM(Ki) 2.1 μM(Ki)
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]

Protocol

Kinase Assay:

[1]

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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
Cell Research:

[1]

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  • Cell lines: HUVECs, and NIH-3T3 cells overexpressing PDGFRβ or EGFR
  • 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 × 106 cells/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


    (Only for Reference)
Animal Research:

[1]

+ Expand
  • Animal Models: Mouse (Female, BALB/c, nu/nu) xenograft models of A375, Colo205, H460, Calu-6, C6, SF763T, and SKOV3TP5 tumor cells
  • Formulation: Dissolved in DMSO
  • Dosages: 75-200 mg/kg
  • Administration: Via i.p. injection or oral gavage once daily.
    (Only for Reference)

Solubility (25°C)

In vitro DMSO 62 mg/mL (199.77 mM)
Water <1 mg/mL
Ethanol <1 mg/mL
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 Information

Molecular Weight 310.35
Formula

C18H18N2O3

CAS No. 252916-29-3
Storage powder
in solvent
Synonyms NSC 702827

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Clinical Trial Information

NCT Number Recruitment Conditions Sponsor/Collaborators Start Date Phases
NCT01465464 Terminated Hepatocellular Carcinoma Taiho Pharmaceutical Co., Ltd. December 2010 Phase 3
NCT00784290 Completed Hepatocellular Carcinoma Taiho Pharmaceutical Co., Ltd. September 2003 Phase 1|Phase 2
NCT00024206 Completed Unspecified Adult Solid Tumor, Protocol Specific National Cancer Institute (NCI) July 2001 Phase 1
NCT00024063 Unknown status Breast Cancer|Colorectal Cancer|Gastric Cancer|Kidney Cancer|Lung Cancer|Multiple Myeloma and Plasma Cell Neoplasm|Pancreatic Cancer|Prostate Cancer Jonsson Comprehensive Cancer Center|National Cancer Institute (NCI) null Phase 1

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Cell Lines Assay Type Concentration Incubation Time Formulation Activity Description PMID