RAF709 is a potent inhibitor of B/C RAF kinase with almost equivalent IC50 values of 0.4 nM for B-RAF and C-RAF.
In cellular assays, the dose−response of pMEK and pERK are measured in Calu-6 cells with EC50 of 0.02 and 0.1 μM with minimal paradoxical activation and inhibition of proliferation with EC50 of 0.95 μM. RAF709 stabilizes BRAF−CRAF dimers with an EC50 of 0.8 μM. Of the 456 kinases tested, RAF709 shows a high level of selectivity, demonstrating greater than 99% on-target binding to BRAF, BRAFV600E, and CRAF at 1 μM and very few off-targets with DDR1 (>99%), DDR2 (86%), FRK (92%), and PDGFRb (96%), the only kinases with binding >80% at 1 μM.
In vivo: In pharmacokinetic experiments, RAF709 has moderate clearance in mouse (35 mL/min/kg) and dog (14 mL/min/kg) and high clearance in rat (50 mL/min/kg). Cmax in mouse (1 μM), dog (0.5 μM), and rat (0.5 μM) reach pharmacologically active concentrations, and acceptable oral availability is observed in mouse (68%), rat (24%), and dog (48%). In the Calu-6 xenograft nude mouse model, treatment with RAF709 results in dose-dependent antitumor activity with 10 mg/kg being subefficacious (%T/C = 92%), 30 mg/kg resulted in measurable antitumor activity (% T/C = 46%), and 200 mg/kg resulted in mean tumor regression of 92%, while the same high dose is not efficacious in the PC3, KRAS WT mode.
|Cell lines||HCT116 cells|
|Preparation method||HCT116 cells are treated with DMSO or RAF709 at indicated concentrations for 1 hour; 1 mmol/L dabrafenib treatment is included for comparison. BRAF/CRAF dimerization is assessed by immunoprecipitating BRAF or CRAF, followed by Western blot analysis of BRAF and CRAF. Levels of pMEK and pERK in whole-cell lysates (WCL) are determined by Western blot analysis. GAPDH level is included as a loading control.|
|Concentrations||0.1, 1, 10 μM|
|Incubation time||1 hour|
|Animal models||Calu-6 model (tumor bearing mice)|
|Dosages||10, 30, or 200 mg/kg|
|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
Ethanol 100 mg/mL
Antitumor Properties of RAF709, a Highly Selective and Potent Inhibitor of RAF Kinase Dimers, in Tumors Driven by Mutant RAS or BRAF.
Shao W, et al. Cancer Res. 2018 Mar 15;78(6):1537-1548. PMID: 29343524.
Design and Discovery of N-(2-Methyl-5'-morpholino-6'-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3'-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers.
Nishiguchi GA, et al. J Med Chem. 2017 Jun 22;60(12):4869-4881. PMID: 28557458.
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L-779450 is a potent, ATP-competitive Raf kinase inhibitor (IC50 =10 nM) that displays > 7, > 30 and > 70-fold selectivity over p38α, GSK3β and Lck respectively.
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