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| 25mg |
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Purity: ≥98%
OSI-930 is an orally bioavailable, potent and selective inhibitor of multi-kinase (Kit, KDR and CSF-1R) with potential antineoplastic activity. It is also potent against Flt-1, c-Raf, and Lck, but exhibits low activity against PDGFRα/β, Flt-3, and Abl. It inhibits Kit, KDR, and CSF-1R with IC50s of 80 nM, 9 nM, and 15 nM, respectively. Thiophene-derived OSI-930 is a tyrosine kinase inhibitor with strong anti-proliferative activity in vitro and strong antitumor efficaciousness in vivo.
| Targets |
KDR (IC50 = 9 nM); Flt-1 (IC50 = 8 nM); Kit (IC50 = 80 nM); PDGFRβ (IC50 = 6900 nM); PDGFRα (IC50 = 3408 nM); CSF-1R (IC50 = 15 nM); c-Raf (IC50 = 41 nM); Flt-3 (IC50 = 1303 nM); Lck (IC50 = 22 nM); Abl (IC50 = 4738 nM)
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
In-house ELISA-based assay techniques (Kit, KDR, PDGFRα, and PDGFRβ) or radiometric techniques are used for protein kinase assays. Poly(Glu:Tyr) was the substrate bound to the 96-well assay plate surface in-house ELISA assays; phosphorylation is then detected using an antiphosphotyrosine antibody conjugated to HRP. Next, by measuring the absorbance at 405/490 nm with ABTS acting as the peroxidase substrate, the bound antibody is quantified. Purified catalytic domains of recombinant kinase, expressed in bacteria or insect cells, are used in all assays. Other enzymes are obtained, but the Kit and EGFR protein needed for internal assays are made on-site. The recombinant Kit protein is first purified as a nonphosphorylated (nonactivated) enzyme with a relatively high Km for ATP (400 μM). It is expressed in insect cells as an NH2-terminal glutathione S-transferase fusion protein. In certain assays, the enzyme is incubated with 1 mM ATP for 1 hour at 30 °C to produce an activated (tyrosine phosphorylated) form. After the majority of the ATP is removed by passing the phosphorylated protein through a desalting column, it is stored at -80 °C in a buffer that contains 50% glycerol. The resulting preparation is much more specific and has a lower ATP Km (25 μM) than the original nonphosphorylated preparation. The nonphosphorylated enzyme is incubated at 30 °C with 200 μM ATP and different concentrations of OSI-930 to measure the inhibition of Kit autophosphorylation by the compound. After removing the aliquots into the SDS-PAGE sample buffer and heating them to 100 °C for five minutes, the reaction is stopped. Next, Kit's level of phosphorylation is assessed using immunoblotting for both total and phosphorylated Kit.
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| Cell Assay |
Cells are seeded into 96-well plates and incubated for two to three days in the presence of OSI-930 at different concentrations for assays of cell proliferation and apoptosis. Using CellTiterGlo, luminescent quantification of the intracellular ATP content is used to determine the inhibition of cell growth. The amount of OSI-930-induced caspase-dependent apoptosis is measured using an enzymatic caspase 3/7 assay. The assay used to measure the inhibition of angiogenesis by OSI-930 is the rat aortic ring endothelial sprout outgrowth. Male rats that have been CO2-euthanized are used to prepare sections of their aorta, which are then cultured in vitro in a collagen matrix with or without OSI-930. Type 1 rat tail collagen is dissolved in 0.1% acetic acid at a concentration of 3 mg/mL to create the collagen matrix. This solution is then mixed with 0.125 volume collagen buffer (0.05 N NaOH, 200 mM HEPES, 260 mM NaHCO3), 0.125 volume of medium 199, 0.0125 volume of 1 M NaOH, and 1% GlutaMax. After adding the appropriate quantity of OSI-930 and 0.5 mL of endothelial basal medium to 0.4 mL of this matrix embedded in aortic rings in six-well plates, the rings are incubated for 10 days. The resulting angiogenic sprout outgrowth is then digitally quantitated from images by measuring the sprout-containing area within a series of concentric rings around the aortic tissue area.
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| Animal Protocol |
HMC-1, NCI-SNU-5, COLO-205 and U251 cells are injected s.c. into the right flank of CD1 nu/nu mice.
≤200 mg/kg Administered via p.o. |
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| References |
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| Additional Infomation |
3-(4-quinolinylmethylamino)-N-[4-(trifluoromethoxy)phenyl]-2-thiophenecarboxamide is an aromatic amide.
OSI-930 is an orally active inhibitor of two clinically validated targets: c-Kit and the vascular endothelial growth factor receptor-2 (VEGFR-2). OSI-930 is designed to target both cancer cell proliferation and blood vessel growth (angiogenesis) in selected tumors. In preclinical studies, OSI-930 shows broad efficacy in tumor models representative of small cell lung cancer, glioblastoma, colorectal, renal, head and neck, non-small cell lung cancer and gastric cancers. Tyrosine Kinase Inhibitor OSI-930 is a selective thiophene-derived tyrosine kinase inhibitor with potential antineoplastic activity. Tyrosine kinase inhibitor OSI-930 inhibits stem cell factor receptor (c-Kit) and the vascular endothelial growth factor receptor 2 (VEGFR2), which may result in the inhibition of both tumor cell proliferation and tumor angiogenesis. Both c-Kit and VEGFR2 are overexpressed in a variety of cancers. Drug Indication Investigated for use/treatment in solid tumors. Mechanism of Action OSI-930 is a multi-targeted tyrosine kinase inhibitor that is designed to act as a potent co-inhibitor of the receptor tyrosine kinases c-Kit and VEGFR-2. The inhibition of the tyrosine kinase activity of Kit is expected to result in reduced cancer cell proliferation and increased cellular apoptosis in tumor types driven by Kit, resulting in inhibition of tumor growth. OSI-930 is also capable of inhibiting VEGFR-2. This receptor is present on endothelial cells and is a key mediator of blood vessel growth in response to the angiogenic growth factor VEGF. This pathway is believed to be the single most important mechanism for recruitment of new blood vessels in nearly all solid tumors. Inhibition of this pathway should therefore impact the growth and metastases of a wide range of angiogenesis-dependent malignancies. |
| Molecular Formula |
C22H16F3N3O2S
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| Molecular Weight |
443.44
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| Exact Mass |
443.091
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| Elemental Analysis |
C, 59.59; H, 3.64; F, 12.85; N, 9.48; O, 7.22; S, 7.23
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| CAS # |
728033-96-3
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| Related CAS # |
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| PubChem CID |
9868037
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
517.4±50.0 °C at 760 mmHg
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| Flash Point |
266.7±30.1 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.687
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| LogP |
5.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
31
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| Complexity |
601
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S1C([H])=C([H])C(=C1C(N([H])C1C([H])=C([H])C(=C([H])C=1[H])OC(F)(F)F)=O)N([H])C([H])([H])C1=C([H])C([H])=NC2=C([H])C([H])=C([H])C([H])=C12
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| InChi Key |
FGTCROZDHDSNIO-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H16F3N3O2S/c23-22(24,25)30-16-7-5-15(6-8-16)28-21(29)20-19(10-12-31-20)27-13-14-9-11-26-18-4-2-1-3-17(14)18/h1-12,27H,13H2,(H,28,29)
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| Chemical Name |
3-(quinolin-4-ylmethylamino)-N-[4-(trifluoromethoxy)phenyl]thiophene-2-carboxamide
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| Synonyms |
OSI-930; OSI930; OSI 930
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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 |
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| 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: ≥ 2.5 mg/mL (5.64 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 25.0 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: ≥ 2.5 mg/mL (5.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% propylene glycol: 5 mg/kg |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2551 mL | 11.2755 mL | 22.5510 mL | |
| 5 mM | 0.4510 mL | 2.2551 mL | 4.5102 mL | |
| 10 mM | 0.2255 mL | 1.1275 mL | 2.2551 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 |
| NCT00603356 | Completed | Drug: OSI-930 and erlotinib | Advanced Solid Tumors | Astellas Pharma Inc | November 2007 | Phase 1 |
| NCT00513851 | Completed | Drug: OSI-930 | Advanced Solid Tumors | Astellas Pharma Inc | April 2006 | Phase 1 |
Inhibition of endothelial cell function by OSI-930 in vitro.Cancer Res. 2006 Jan 15;66(2):1015-24. |
Pharmacokinetic/pharmacodynamic relationship of OSI-930 in the HMC-1 tumor xenograft model and correlation with antitumor activity. Cancer Res. 2006 Jan 15;66(2):1015-24. |
Pharmacodynamic effects of OSI-930 and correlation with antitumor activity. Cancer Res. 2006 Jan 15;66(2):1015-24. |
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