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OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.
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Source | Acta Haematol (2014). Figure 2. OSI-930 |
| Method | ELISA-based assay | |
| Cell Lines | NCI-H526 cells, HUVECs and NIH-3T3 cells | |
| Concentrations | 100 nmol/L | |
| Incubation Time | 2 to 3 h | |
| Results | The concentration of OSI-930 that induced these phenotypic effects was comparable to that required to inhibit Kit phosphorylation in the HMC-1 cell line under the same culture conditions |
| Cell Experiment | |
|---|---|
| Cell lines | HMC-1 cell line |
| Preparation method | For assays of cell proliferation, cells were 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 was determined by luminescent quantitation of the intracellular ATP content using CellTiterGlo (Promega, Madison, WI). |
| Concentrations | 0~100nM |
| Incubation time | 2-3 days |
| Animal Experiment | |
|---|---|
| Animal models | HMC-1 tumor xenograft model |
| Formulation | either Labrafil M 1944 CS (Gattefossé) or polyethylene glycol (PEG)-400/water (50:50)] at an appropriate concentration to deliver the desired dose at 20 mL/kg |
| Dosages | a single oral dose of 5, 10, 25, or 50 mg/kg |
| Administration | oral gavage |
| Molecular Weight | 443.44 |
| Formula | C22H16F3N3O2S |
| CAS Number | 728033-96-3 |
| Solubility (25°C) | DMSO 45 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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