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.
|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 models||mice bearing HCT116, A549 or MDAMB231 xenografts|
|Dosages||12 mg/kg daily over 14 d (6 d on, 2 d off, 6 d on)|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|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.
|Solubility||DMSO ≥100 mg/mL|
RAF265, a dual BRAF and VEGFR2 inhibitor, prevents osteoclast formation and resorption. Therapeutic implications.
Garcia-Gomez et al. Invest New Drugs. 2012 Jul 7. PMID: 22773056.
RAF265 inhibits the growth of advanced human melanoma tumors.
Su et al. Clin Cancer Res. 2012 Apr 15;18(8):2184-98. PMID: 22351689.
The novel Raf inhibitor Raf265 decreases Bcl-2 levels and confers TRAIL-sensitivity to neuroendocrine tumour cells.
Zitzmann et al. Endocr Relat Cancer. 2011 Mar 21;18(2):277-85. PMID: 21317202.
Dependence on phosphoinositide 3-kinase and RAS-RAF pathways drive the activity of RAF265, a novel RAF/VEGFR2 inhibitor, and RAD001 (Everolimus) in combination.
Mordant P, et al. Mol Cancer Ther. 2010 Feb;9(2):358-68. PMID: 20124452.
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GW5074 is a potent and selective c-Raf inhibitor with IC50 of 9 nM, no effect on the activities of JNK1/2/3, MEK1, MKK6/7, CDK1/2, c-Src, p38 MAP, VEGFR2 or c-Fms is noted.
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