RAF265 (CHIR-265) is a novel, orally bioavailable dual inhibitor of RAF kinase and VEGFR2. RAF265 significantly enhanced TRAIL sensitivity in NCI-H727 and CM insulinoma cells by blocking Raf-MEK-Erk signalling. RAF265 strongly decreased Bcl-2 levels in those cell lines susceptible to its TRAIL-sensitizing action. RAF265 impaired in vitro differentiation of PBMCs to OCs induced by receptor activator of NF-kB ligand (RANKL) and M-CSF (IC(50) ≈ 160 nM). In parallel, RAF265 exerted a potent inhibition of OC resorptive capacity (IC(50) ≈ 20 nM). Moreover, RAF265 exhibits reduced pMEK1, reduced proliferation based upon reduced Ki-67, cyclin D1 and polo-like kinase1 levels, and induction of the apoptosis mediator BCL2-like 11. Using Raf-MEK-Erk pathway inhibitors and TRAIL together might offer a novel therapeutic strategy in NET disease.
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Source | Mol Cancer (2015). Figure 1.RAF265 |
| Method | MTT assay | |
| Cell Lines | HT29 and HCT116 cells | |
| Concentrations | 0–50 μM | |
| Incubation Time | 48 h | |
| Results | When treated with 1 μM Raf265 for 3 weeks, the number of colony formed reduced from 38.6 ± 6.5 and 28.3 ± 3.5 to 1.67 ± 1.15 and 0.67 ± 0.58 colonies for HT29 and HCT116 cells, respectively. |
| Cell Experiment | |
|---|---|
| Cell lines | HCT116, HT29, and MDAMB231 cell lines |
| Preparation method | Cell Viability Assay The MTT assay and Bliss additivism model were used to assess the effect of the combination on cell viability. In each well of a 96-well plate, 1 × 104 cells were grown in 200 μL of medium. After 24 h, RAD001, RAF265, or the combination was added to achieve a final concentration of 0.1 to 10 nmol/L and 0.1 to 10 μmol/L, respectively. After 48 h of treatment, 20 μL of 5 mg mL−1 MTT (Organics Research, Inc.) solution in PBS was added to each well. After 4 h, supernatant was removed and formazan crystals were discarded in 200 μL of DMSO. Absorbance was then measured at 595 nm using an absorbance plate reader (Bio-Rad Microplate Reader). Data are expressed as the percentage of viable cells in treated relative to nontreated conditions. |
| Concentrations | 0.1 to 10 μM |
| Incubation time | 48 h |
| Animal Experiment | |
|---|---|
| Animal models | mice bearing HCT116, A549 or MDAMB231 xenografts |
| Formulation | DMSO/PBS |
| Dosages | 12 mg/kg daily over 14 d (6 d on, 2 d off, 6 d on) |
| Administration | orally |
| Molecular Weight | 518.41 |
| Formula | C24H16F6N6O |
| CAS Number | 927880-90-8 |
| Solubility (25°C) | DMSO ≥90 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 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 Compound A of 10 mg/kg.
[2] Su et al. Clin Cancer Res. RAF265 inhibits the growth of advanced human melanoma tumors.
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