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5mg |
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10mg |
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25mg |
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50mg |
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100mg |
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250mg |
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Purity: ≥98%
Orantinib (formerly SU6668; TSU-68; NSC-702827; TSU 68; SU-6668) is a potent, orally bioavailable and multi-targeted receptor tyrosine kinase/RTK inhibitor with potential antineoplastic activity. In a cell-free assay, orantinib primarily inhibits the autophosphorylation of PDGFR with a Ki of 8 nM. It also potently inhibits the trans-phosphorylation of Flk-1 and FGFR1, with little to no activity against other kinases like EGFR, IGF-1R, Met, Src, Lck, Zap70, Abl, and CDK2. Additionally, orantinib has the potential to treat hepatocellular carcinoma and is currently undergoing clinical trials.
Targets |
PDGFRβ (Ki = 8 nM); FGFR1 (Ki = 1.2 μM); Flt-1 (Ki = 2.1 μM)
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ln Vitro |
Orantinib (SU6668; 0.03-10 μM) inhibits the tyrosine phosphorylation of KDR in VEGF-stimulated HUVECs and prevents PDGF-stimulated PDGFRβ tyrosine phosphorylation in NIH-3T3 cells that overexpress PDGFRβ. The phosphorylation of the FGFR1 substrate 2 is inhibited by orantinib (≥10 μM) when it is exposed to acidic FGF. Nonetheless, in NIH-3T3 cells overexpressing EGFR, orantinib (up to 100 μM) has no effect on EGF-stimulated EGFR tyrosine phosphorylation. Moreover, orantinib blocks HUVECs' ability to proliferate when stimulated by VEGF and FGF, with mean IC50 values of 0.34 μM and 9.6 μM, respectively[1]. Orantinib (SU6668) inhibits both ERK1/2 phosphorylation and the tyrosine autophosphorylation of the stem cell factor (SCF) receptor, c-kit, in human myeloid leukemia MO7E cells, with an IC50 of 0.1-1 μM. Furthermore, orantinib induces apoptosis and, at an IC50 of 0.29 μM, suppresses the proliferation of MO7E cells induced by SCF[2].
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ln Vivo |
Orantinib (SU6668; 75-200 mg/kg) inhibits the growth of various tumor types, including A375, Colo205, H460, Calu-6, C6, SF763T, and SKOV3TP5 cells, in xenograft models in athymic mice. C6 glioma xenograft tumor angiogenesis is likewise inhibited by orantinib (75 mg/kg)[1]. Orantinib (200 mg/kg) reduces average vessel permeability and average fractional plasma volume in the tumor rim and core of an HT29 human colon carcinoma tumor model. Around the edges of carcinomas, orantinib promotes aberrant stromal development[3]. In addition, a rabbit VX2 liver tumor model shows that Orantinib (TSU-68; 200 mg/kg) enhances the effects of chemotherapy infusion[4].
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Enzyme Assay |
Tyrosine kinase assays are used in 96-well microtiter plates that have been precoated (20 μg/well) in PBS and incubated overnight at 4 °C with the peptide substrate poly-Glu,Tyr (4:1). The purpose of these assays is to quantify the trans-phosphorylation activity of Flk-1 and FGFR1. One to five percent (w/v) BSA in PBS is used to block excess protein binding sites. The microtiter wells are then filled with purified GST-FGFR1 (kinase domain) or GST-Flk-1 (cytoplasmic domain) fusion proteins in a 2 × concentration kinase dilution buffer that contains 40 μM NaVO4, 50 mM NaCl, 100 mM HEPES, and 0.02% (w/v) BSA. For GST-Flk-1 and GST-FGFR1, the final enzyme concentration is 50 ng/mL. SU6668 is diluted 1:25 in H2O after being dissolved in DMSO at 100× the final required concentration. Each reaction well is then filled with 25 μL of diluted SU6668. Different concentrations of ATP are added to a solution of MnCl2 to start the kinase reaction. The final concentration of MnCl2 is 10 mM, and the final ATP concentrations span the Km for the enzyme. Before adding EDTA to stop the reaction, the plates are incubated for five to fifteen minutes at room temperature. TBST is then used to wash the plates three times. In TBST containing 0.5% (w/v) BSA, 0.025% (w/v) nonfat dry milk, and 100 μM NaVO4, rabbit polyclonal antiphosphotyrosine antisera are diluted 1: 10,000 and added to the wells. The incubation process lasts for one hour at 37 °C. Next, goat anti-rabbit antisera conjugated with HRP is added to the plates after three TBST washes. Three TBST washes are performed after the plates are incubated for an hour at 37 °C. After adding 2,2 to each well, the amount of phosphotyrosine is measured.
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Cell Assay |
In DMEM containing 10% (v/v) FBS, cells (HUVECs and NIH-3T3 cells overexpressing PDGFRβ or EGFR) are seeded (3 × 105 cells/35-mm well), grown to confluence, and then quiesced in DMEM containing 0.1% serum for two hours prior to drug treatment. After being seeded at a density of 2 × 106 cells/10-cm plate, HUVECs are grown to confluence in endothelial cell growth media and subsequently quiesce for 24 hours in endothelial cell basal media containing 0.5% FBS prior to drug treatment. Before being stimulated with ligand (100 ng/mL) for 10 minutes, all cell lines are incubated with SU6668 for 1 hour.
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Animal Protocol |
Mouse (Female, BALB/c, nu/nu) xenograft models of A375, Colo205, H460, Calu-6, C6, SF763T, and SKOV3TP5 tumor cells
75-200 mg/kg Via i.p. injection or oral gavage once daily. |
References |
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Molecular Formula |
C18H18N2O3
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Molecular Weight |
310.35
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Exact Mass |
310.13
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Elemental Analysis |
C, 69.66; H, 5.85; N, 9.03; O, 15.47
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CAS # |
252916-29-3
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Related CAS # |
(Z)-Orantinib;210644-62-5
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Appearance |
Solid powder
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SMILES |
CC1=C(NC(=C1CCC(=O)O)C)/C=C\2/C3=CC=CC=C3NC2=O
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InChi Key |
NHFDRBXTEDBWCZ-ZROIWOOFSA-N
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InChi Code |
InChI=1S/C18H18N2O3/c1-10-12(7-8-17(21)22)11(2)19-16(10)9-14-13-5-3-4-6-15(13)20-18(14)23/h3-6,9,19H,7-8H2,1-2H3,(H,20,23)(H,21,22)/b14-9-
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Chemical Name |
3-[2,4-dimethyl-5-[(Z)-(2-oxo-1H-indol-3-ylidene)methyl]-1H-pyrrol-3-yl]propanoic acid
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Synonyms |
Orantinib; NSC 702827; NSC-702827; NSC702827; TSU68; TSU-68; SU-6668; SU 6668; SU6668; NSC702827; TSU 68
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HS Tariff Code |
2934.99.9001
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Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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Solubility (In Vitro) |
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 10 mg/mL (32.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 100.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 1% DMSO+30% polyethylene glycol+1% Tween 80: 30 mg/mL  (Please use freshly prepared in vivo formulations for optimal results.) |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 3.2222 mL | 16.1108 mL | 32.2217 mL | |
5 mM | 0.6444 mL | 3.2222 mL | 6.4443 mL | |
10 mM | 0.3222 mL | 1.6111 mL | 3.2222 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration: mg/mL;
Method for preparing DMSO stock solution: mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation::Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O,mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
NCT00024206 | Completed | Other: pharmacological study Drug: orantinib |
Unspecified Adult Solid Tumor, Protocol Specific |
National Cancer Institute (NCI) |
July 2001 | Phase 1 |
NCT00784290 | Completed | Drug: Orantinib (TSU-68) |
Hepatocellular Carcinoma | Taiho Pharmaceutical Co., Ltd. | September 2003 | Phase 1 Phase 2 |
NCT01465464 | Terminated | Drug: Orantinib (TSU-68) Drug: Placebo |
Hepatocellular Carcinoma | Taiho Pharmaceutical Co., Ltd. | December 2010 | Phase 3 |
Efficacy of SU6668 on s.c. A431 xenograft growth in athymic mice.Cancer Res.2000Aug 1;60(15):4152-60. td> |
Effect of SU6668 on tumor xenograft angiogenesis.Cancer Res.2000Aug 1;60(15):4152-60. td> |
Efficacy of SU6668 against established A431 s.c. xenografts in athymic mice. A, SU6668 regresses established tumors in athymic mice.Cancer Res.2000Aug 1;60(15):4152-60. td> |
A, HUVECs;B, NIH-3T3 cells overexpressing PDGFRβ;C, NIH-3T3 cells;D, NIH-3T3 cells overexpressing EGFR.Cancer Res.2000Aug 1;60(15):4152-60. td> |
Inhibition of endothelial cell proliferation stimulated by either VEGF or FGF.Cancer Res.2000Aug 1;60(15):4152-60. td> |
Crystal structure of SU6668 in FGFR1 (left panel) and homology model of SU6668 in PDGFR (right panel).Cancer Res.2000Aug 1;60(15):4152-60. td> |