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Purity: ≥98%
RAF709 is a novel and potent inhibitor of the Raf kinase B/C isoforms (compound example 131 from patent WO2014151616A1) developed through a hypothesis-driven approach focusing on drug-like properties. For c-Raf and b-Raf, the IC50 values are, respectively, 0.5 and 1.8 nM. It is effective in a KRAS mutant xenograft model, soluble, and kinase selective, and it demonstrated a high level of selectivity over other kinases. Additionally, RAF709 showed at 1 μM that it bound to BRAF, BRAFV600E, and CRAF with greater than 99% on-target affinity and little to no off-target affinity for DDR1 (>99%), DDR2 (86%), FRK (92%), and PDGFRb (96%). When RAF709 and a MEK inhibitor are used together, KRASmut tumors exhibit improved antitumor activity.
| Targets |
C-Raf (IC50 = 0.4 nM); BRAF(V600E) (IC50 = 1 nM); B-Raf (IC50 = 1.5 nM)
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| ln Vitro |
RAF709 stabilizes BRAF-CRAF dimers with an EC50 of 0.8 μM. The cellular assays used to measure the dose-response of pMEK and pERK in Calu-6 cells used EC50 values of 0.02 and 0.1 μM with minimal paradoxical activation and 0.95 M with proliferative inhibition[1].
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| ln Vivo |
RAF709 proves to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model. In Calu-6 tumors, RAF709 causes a dose-dependent inhibition of pERK and dose-proportional increases in plasma exposure. Treatment with RAF709 produces dose-dependent antitumor activity, with 10 mg/kg being subefficacious (%T/C=92%), 30 mg/kg producing measurable antitumor activity (%T/C=46%), and 200 mg/kg producing mean tumor regression of 92%, whereas the same high dose is ineffective in the PC3, KRAS WT model[1].
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| Enzyme Assay |
The MEK1 protein substrate, which carries the K97R mutation, was used as the substrate for the CRAF kinase assay along with 10 nM kinase-dead MEK1, 3 μM ATP, and 10 pM CRAF Y340E/Y341E. The reaction buffer contained 1 mM DTT, 50 mM Tris pH 7.5, 10 μL MgCl2, 0.05% BSA, 50 mM NaCl, and 0.01% Tween-20. The reactions took place in white 384 shallow well plates with a volume of 10 μL at room temperature for 40 minutes before being quenched with a solution of 5 μL per well (50 mM Tris pH 7.5, 50 mM EDTA). Reactions that had reached their end were given 5 μL/well of detection reagents, which included 50 mM Tris pH 7.5, 0.01% Tween-20, antiphospho MEK1/2 S217/S221 antibody diluted 1:1,000, 0.01 mg/mL of AlphaScreen Protein A-coated acceptor beads, and 0.01 mg/mL of streptavidin-coated donor beads. After a night of incubation at room temperature, plates were read in an EnVision plate reader. Compounds were tested in 16-point, 3-fold format in compound inhibition studies over a concentration range of 25 μM to 1.74 × 10−6 μM. The final concentration of DMSO was 0.5%. Before adding substrates to begin the reaction, compounds were given a 30-minute preincubation with CRAF. The IC50 of the compounds was determined by fitting the data on inhibition to a four-parameter logistic equation.
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| Cell Assay |
For 1 hour, HCT116 cells are treated with DMSO or RAF709 at the indicated concentrations; a comparison treatment with 1 mmol/L dabrafenib is also included. BRAF or CRAF is immunoprecipitated, and the BRAF and CRAF proteins are then analyzed on a Western blot to determine whether BRAF/CRAF dimerization has occurred. Western blot analysis is used to quantify the amounts of pMEK and pERK in whole-cell lysates (WCL). GAPDH level is used as a loading control.
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| Animal Protocol |
Calu-6 model (tumor bearing mice)
10, 30, or 200 mg/kg oral administration |
| References |
| Molecular Formula |
C28H29F3N4O4
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| Molecular Weight |
542.55
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| Exact Mass |
542.21
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| Elemental Analysis |
C, 61.99; H, 5.39; F, 10.50; N, 10.33; O, 11.80
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| CAS # |
1628838-42-5
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
CC1=C(C=C(C=N1)NC(=O)C2=CC(=CC=C2)C(F)(F)F)C3=CC(=C(N=C3)OC4CCOCC4)N5CCOCC5
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| InChi Key |
FYNMINFUAIDIFL-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H29F3N4O4/c1-18-24(15-22(17-32-18)34-26(36)19-3-2-4-21(13-19)28(29,30)31)20-14-25(35-7-11-38-12-8-35)27(33-16-20)39-23-5-9-37-10-6-23/h2-4,13-17,23H,5-12H2,1H3,(H,34,36)
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| Chemical Name |
N-[6-methyl-5-[5-morpholin-4-yl-6-(oxan-4-yloxy)pyridin-3-yl]pyridin-3-yl]-3-(trifluoromethyl)benzamide
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| Synonyms |
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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 |
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| 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: ≥ 2.5 mg/mL (4.61 mM) (saturation unknown) in 10% DMSO + 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 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL 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: ≥ 2.5 mg/mL (4.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO 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: ≥ 2.5 mg/mL (4.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8431 mL | 9.2157 mL | 18.4315 mL | |
| 5 mM | 0.3686 mL | 1.8431 mL | 3.6863 mL | |
| 10 mM | 0.1843 mL | 0.9216 mL | 1.8431 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.
RAF709 exhibits highly selective activity targeting both BRAF and CRAF kinases.Cancer Res.2018 Mar 15;78(6):1537-1548. |
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RAF709 is an effective inhibitor of BRAF monomers and RAF dimers.Cancer Res.2018 Mar 15;78(6):1537-1548. |
RAF709 inhibits oncogenic signaling and proliferation in tumor cells with BRAF, NRAS, and KRAS mutations, with minimal paradoxical activation.Cancer Res.2018 Mar 15;78(6):1537-1548. |
RAF709 demonstrates selective anticancer activity in KRASmutNSCLC cells.Cancer Res.2018 Mar 15;78(6):1537-1548. |
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RAF709 exhibits greater antiproliferative activity in cancer cell lines harboring BRAF or RAS mutations.Cancer Res.2018 Mar 15;78(6):1537-1548. |
RAF709 demonstrates antitumor activity in tumors harboring RAS mutationsin vivo.Cancer Res.2018 Mar 15;78(6):1537-1548. |
RAF709 in combination with a MEK inhibitor provides enhanced antitumor activity in KRASmuttumors.Cancer Res.2018 Mar 15;78(6):1537-1548. |
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 J Med Chem.2017 Jun 22;60(12):4869-4881. |
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