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Purity: ≥98%
RAF265 (formerly also known as CHIR265; RAF 265; RAF-265) is an orally bioavailable multi-kinase inhibitor with potential antitumor activity. With an IC50 range of 3–60 nM, it inhibits a number of kinases, including BRAFV600E, BRAF (wild-type), c-RAF, VEGFR2, PDGFR, CSF 1R, RET, c-KIT, SRC, and STE20. In BRAFV600E melanoma and colorectal cancer xenograft models, RAF26 shows notable anti-proliferative activity in vitro and strong in vivo antitumor efficacy.
| Targets |
VEGFR2 (EC50 = 30 nM); B-Raf (IC50 = 3 nM-60 nM)
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| ln Vitro |
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| Enzyme Assay |
In assay buffer (50 mM Tris, pH 7.5, 15 mM MgCl2, 0.1 mM EDTA, and 1 mM DTT), Raf and Mek are combined at 2 × final concentrations. 15 μL is then dispensed per well in polypropylene assay plates. The background levels in the wells with Mek and DMSO but no Raf are measured. 3 μL of 10 × RAF265 diluted in 100% DMSO is added to the Raf/Mek containing wells. To initiate the raf kinase activity reaction, add 12 μL of diluted 2.5 × 33P-ATP per well in assay buffer. The reactions are halted by adding 70 μL of stop reagent (30 mM EDTA) after 45–60 minutes. After five minutes of pre-wetting with 70% ethanol, filtration plates are rinsed with wash buffer. Following that, samples (90 μL) are moved from the reaction wells to the filtration plates. The Millipore filtration apparatus is used to wash the filtration plates six times with wash buffer. After the plates are dried, 100 μL of scintillation fluid is added to each well. After that, the CPM is calculated with a Wallac Microbeta 1450 reader.
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| Cell Assay |
The Bliss additivism model and the MTT assay are used to evaluate how RAF265 affects cell viability. A total of 1 × 104 cells are grown in 200 μL of medium in each well of a 96-well plate. To reach a final concentration of 0.1 to 10 μM, RAF265 is added after a 24-hour period. 20 μL of a 5 mg/mL MTT solution in PBS is added to each well following a 48-hour treatment period. The formazan crystals are disposed of in 200 μL of DMSO after the supernatant is extracted after 4 hours. Next, using an absorbance plate reader, absorbance is measured at 595 nm. The percentage of viable cells is used to express data.
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| Animal Protocol |
Mice: In vivo testing is also done to evaluate the combination's effectiveness. The flank region of 6-week-old female athymic mice receives a single subcutaneous injection of 3×106 A549, H460, HCT116, or MDAMB231 cells. Treatment options for the mice are vehicle, RAD001 (12 mg/kg daily), RAF265 (12 mg/kg daily), or both, and they are randomized into four groups (n=7/group) once the tumors reach 50 mm3. The drug combination is administered concurrently, and all medications are administered over a period of 14 days (6 days on, 2 days off, and 6 days on). Both drugs are given to control mice in their appropriate delivery systems. Tumor volumes and animal weights are recorded twice a week, and the results are expressed in relation to the original tumor volume. It is recorded how long it takes for a tumor to reach a relative volume ten times its initial volume. Tumor growth curve, growth delay, and percentage of tumor volume inhibition are used to evaluate the efficacy of drugs. To show how the relative tumor size has changed over time, a tumor growth curve is used. An algorithm is used to compute the tumor volume inhibition percentage (TVI%).
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| References | ||
| Additional Infomation |
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine is an aromatic ether.
B-Raf/VEGFR-2 Inhibitor RAF265 is an orally bioavailable small molecule with potential antineoplastic activity. CHIR-265 binds and inhibits Raf kinases, which may result in a reduction of tumor cell growth and proliferation, and tumor cell death. In addition, this agent inhibits vascular endothelial growth factor receptor type 2 (VEGFR-2), thereby disrupting tumor angiogenesis. Raf kinases are critical enzymes in the Ras/Raf/MEK/ERK signaling pathway and are frequently upregulated in neoplasms. Drug Indication Investigated for use/treatment in melanoma. Mechanism of Action CHIR-265 binds and inhibits Raf kinases, which may result in a reduction of tumor cell growth and proliferation, and tumor cell death. In addition, this agent inhibits vascular endothelial growth factor receptor type 2 (VEGFR-2), thereby disrupting tumor angiogenesis. Raf kinases are critical enzymes in the Ras/Raf/MEK/ERK signaling pathway and are frequently upregulated in neoplasms. |
| Molecular Formula |
C24H16F6N6O
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| Molecular Weight |
518.41
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| Exact Mass |
518.128
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| Elemental Analysis |
C, 55.60; H, 3.11; F, 21.99; N, 16.21; O, 3.09
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| CAS # |
927880-90-8
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| Related CAS # |
927880-90-8;
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| PubChem CID |
11656518
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| Appearance |
White to khaki solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
667.6±65.0 °C at 760 mmHg
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| Flash Point |
357.5±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.622
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| LogP |
6.03
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
37
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| Complexity |
763
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| Defined Atom Stereocenter Count |
0
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| SMILES |
FC(C1C=CC(NC2N(C)C3C(=CC(=CC=3)OC3C=C(C4NC(C(F)(F)F)=CN=4)N=CC=3)N=2)=CC=1)(F)F
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| InChi Key |
YABJJWZLRMPFSI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H16F6N6O/c1-36-19-7-6-15(10-17(19)34-22(36)33-14-4-2-13(3-5-14)23(25,26)27)37-16-8-9-31-18(11-16)21-32-12-20(35-21)24(28,29)30/h2-12H,1H3,(H,32,35)(H,33,34)
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| Chemical Name |
1-methyl-5-[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]pyridin-4-yl]oxy-N-[4-(trifluoromethyl)phenyl]benzimidazol-2-amine
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| Synonyms |
RAF 265; RAF265; CHIR-265; CHIR 265; RAF-265; CHIR265
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1 mg/mL (1.93 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear EtOH stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 1 mg/mL (1.93 mM) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 1 mg/mL (1.93 mM) in 10% EtOH + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5% propylene glycol: 30 mg/kg |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9290 mL | 9.6449 mL | 19.2898 mL | |
| 5 mM | 0.3858 mL | 1.9290 mL | 3.8580 mL | |
| 10 mM | 0.1929 mL | 0.9645 mL | 1.9290 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01352273 | Completed | Drug: MEK162 + RAF265 | Advanced Solid Tumors | Array Biopharma, now a wholly owned subsidiary of Pfizer |
June 2011 | Phase 1 |
| NCT00304525 | Completed | Drug: RAF265 | Metastatic Melanoma | Novartis Pharmaceuticals | April 2006 | Phase 1 Phase 2 |
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