OSI-930

Catalog No.S1220

OSI-930 is a potent inhibitor of Kit, KDR and CSF-1R with IC50 of 80 nM, 9 nM and 15 nM, respectively; also potent to Flt-1, c-Raf and Lck and low activity against PDGFRα/β, Flt-3 and Abl. Phase 1.

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OSI-930 Chemical Structure

OSI-930 Chemical Structure
Molecular Weight: 443.44

Validation & Quality Control

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Product Information

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  • Research Area
  • Inhibition Profile

Product Description

Biological Activity

Description OSI-930 is a potent inhibitor of Kit, KDR and CSF-1R with IC50 of 80 nM, 9 nM and 15 nM, respectively; also potent to Flt-1, c-Raf and Lck and low activity against PDGFRα/β, Flt-3 and Abl. Phase 1.
Targets FLT1 [1] KDR [1] CSF-1R [1] LCK [1]

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IC50 8 nM 9 nM 15 nM 22 nM
In vitro OSI-930 inhibits the cell proliferation in the HMC-1 cell line with IC50 of 14 nM without significant effect on growth of the COLO-205 cell line that does not express a constitutively active mutant receptor tyrosine kinase. Moreover, OSI-930 also induces apoptosis in HMC-1 cell line with EC50 of 34 nM. [1] A recent study shows that OSI-930 inactivates purified, recombinant cytochrome P450 (P450) 3A4 with a Ki of 24 μM in a time- and concentration-dependent mode. [2]
In vivo OSI-930, administrated at the maximally efficacious dose of 200 mg/kg by oral gavage, exhibits potent antitumor activity in a broad range of preclinical xenograft models including HMC-1, NCI-SNU-5, COLO-205 and U251 xenograft models. [1]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Protein kinase assays Protein kinase assays are either done in-house by ELISA-based assay methods (Kit, KDR, PDGFRα, and PDGFRβ) or by a radiometric method. In-house ELISA assays used poly(Glu:Tyr) as the substrate bound to the surface of 96-well assay plates; phosphorylation is then detected using an antiphosphotyrosine antibody conjugated to HRP. The bound antibody is then quantitated using ABTS as the peroxidase substrate by measuring the absorbance at 405/490 nm. All assays uses purified recombinant kinase catalytic domains that are either expressed in insect cells or in bacteria. The Kit and EGFR protein used for in-house assays are prepared internally; other enzymes are obtained. Recombinant Kit protein is expressed as an NH2-terminal glutathione S-transferase fusion protein in insect cells and is initially purified as a nonphosphorylated (nonactivated) enzyme with a relatively high Km for ATP (400 μM). In some assays, an activated (tyrosine phosphorylated) form of the enzyme is prepared by incubation with 1 mM ATP for 1 hour at 30 °C. The phosphorylated protein is then passed through a desalting column to remove the majority of the ATP and stored at −80 °C in buffer containing 50% glycerol. The resultant preparation has a considerably higher specific activity and a lower Km for ATP (25 μM) than the initial nonphosphorylated preparation. The inhibition of Kit autophosphorylation by OSI-930 is assayed by incubation of the nonphosphorylated enzyme at 30 °C in the presence of 200 μM ATP and various concentrations of OSI-930. The reaction is stopped by removal of aliquots into SDS-PAGE sample buffer followed by heating to 100 °C for 5 minutes. The degree of phosphorylation of Kit is then determined by immunoblotting for both total Kit and phosphorylated Kit.

Cell Assay: [1]

Cell lines HMC-1 and COLO-205
Concentrations 0--1 μM
Incubation Time 48 hours
Method For assays of cell proliferation and apoptosis, cells are seeded into 96-well plates and incubated for 2 to 3 days in the presence of OSI-930 at various concentrations. Inhibition of cell growth is determined by luminescent quantitation of the intracellular ATP content using CellTiterGlo. Induction of caspase-dependent apoptosis by OSI-930 is quantitated by an enzymatic caspase 3/7 assay. Inhibition of angiogenesis by OSI-930 is monitored using the rat aortic ring endothelial sprout outgrowth assay. Sections of aorta are prepared from CO2-euthanized male rats and cultured in vitro in a collagen matrix in the presence or absence of OSI-930. The collagen matrix is prepared from type 1 rat tail collagen solubilized in 0.1% acetic acid at 3 mg/mL, which is combined 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. Aortic rings are embedded in 0.4 mL of this matrix in six-well plates, to which 0.5 mL endothelial basal medium and the appropriate amount of OSI-930 is added; the rings are then incubated for 10 days and the resultant angiogenic sprout outgrowth is digitally quantitated from images by measurement of the sprout-containing area within a series of concentric rings around the aortic tissue area.

Animal Study: [1]

Animal Models HMC-1, NCI-SNU-5, COLO-205 and U251 cells are injected s.c. into the right flank of CD1 nu/nu mice.
Formulation OSI-930 is dissolved in either Labrafil M 1944 CS or polyethylene glycol (PEG)-400/water (50:50).
Dosages ≤200 mg/kg
Administration Administered via p.o.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Garton AJ, et al. Cancer Res. 2006, 66(2):1015-1024.

[2] Lin HL, et al. Drug Metab Dispos. 2011, 39(2), 345-350.

Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-06-25)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT00603356 Completed Advanced Solid Tumors Astellas Pharma Inc|OSI Pharmaceuticals November 2007 Phase 1
NCT00513851 Completed Advanced Solid Tumors Astellas Pharma Inc|OSI Pharmaceuticals April 2006 Phase 1

Chemical Information

Download OSI-930 SDF
Molecular Weight (MW) 443.44
Formula

C22H16F3N3O2S

CAS No. 728033-96-3
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 89 mg/mL (200.7 mM)
Ethanol 3 mg/mL (6.76 mM)
Water <1 mg/mL (<1 mM)
In vivo 30% PEG400+0.5% Tween80+5% propylene glycol 5 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 3-​[(4-​quinolinylmethyl)​amino]​-​N-​[4-​(trifluoromethoxy)​phenyl]​-2-​thiophenecarboxamide

Customer Product Validation(3)


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Rating
Source BMC Microbiol 2013 13, 249. OSI-930 purchased from Selleck
Method RelA/p65 activation assays
Cell Lines RE-luc2P-HEK293 cells
Concentrations 1 uM
Incubation Time 16 h
Results The drug imaging experiment, analysing liver sections derived from treated mice, resulted in corresponding findings. The measurement of pirfenidone with CHCa matrix revealed visualisation of the drug peak in both, the liver of the treated animal as well as in the liver of the negative control, indicating an overlapping of the drug signal with a background signal of the tissue.

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Rating
Source OSI-930 purchased from Selleck
Method
Cell Lines HEK293-pcDNA3.1/HEK293-ABCG2-482-R2 cells
Concentrations 10 µM
Incubation Time
Results Table 2. shows the reversal effect of OSI-930 and Fumitremorgin C (FTC) on the cytotoxicity of mitoxantrone to HEK293/pcDNA3.1 and HEK293-ABCG2-482-R2.

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Rating
Source Dr. Yong-Weon Yi from Georgetown University Medical Center. OSI-930 purchased from Selleck
Method MTT assays
Cell Lines MDA-MB-231 cells, MDA-MB-436 cells
Concentrations 0-10 μM
Incubation Time 72 h
Results OSI-930 treatments reduced MDA-MB-231 cells and MDA-MB-436 cells growth in a dose-dependent manner.

Tech Support

Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.

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