Home Protein Tyrosine Kinase c-Kit inhibitor OSI-930

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OSI-930 c-Kit inhibitor

Cat.No.S1220

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

Chemical Structure

Molecular Weight: 443.44

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Quality Control

Batch: Purity: 99.92%
99.92

Solubility

In vitro
Batch:

DMSO : 89 mg/mL (200.7 mM)
(Moisture-contaminated DMSO may reduce solubility. Use fresh, anhydrous DMSO.)

Ethanol : 3 mg/mL

Water : Insoluble

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In vivo
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Chemical Information, Storage & Stability

Molecular Weight 443.44 Formula

C22H16F3N3O2S

 Storage (From the date of receipt)
CAS No. 728033-96-3 Download SDF Storage of Stock Solutions

Synonyms N/A Smiles C1=CC=C2C(=C1)C(=CC=N2)CNC3=C(SC=C3)C(=O)NC4=CC=C(C=C4)OC(F)(F)F

Mechanism of Action

Targets/IC50/Ki
FLT1
(Cell-free assay)
8 nM
KDR
(Cell-free assay)
9 nM
CSF-1R
(Cell-free assay)
15 nM
LCK
(Cell-free assay)
22 nM
C-Raf
(Cell-free assay)
41 nM
Kit
(Cell-free assay)
80 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, this compound also induces apoptosis in HMC-1 cell line with EC50 of 34 nM. A recent study shows that this chemical inactivates purified, recombinant cytochrome P450 (P450) 3A4 with a Ki of 24 μM in a time- and concentration-dependent mode.
Kinase Assay
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 this compound is assayed by incubation of the nonphosphorylated enzyme at 30 °C in the presence of 200 μM ATP and various concentrations of this chemical. 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.
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.
References

Clinical Trial Information

(data from https://clinicaltrials.gov, updated on 2024-05-22)

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

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