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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 Experiment | |
|---|---|
| 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 Experiment | |
|---|---|
| Animal models | Calu-6 model (tumor bearing mice) |
| Formulation | 20% Captisol |
| Dosages | 10, 30, or 200 mg/kg |
| Administration | oral administration |
| Molecular Weight | 542.55 |
| Formula | C28H29F3N4O4 |
| CAS Number | 1628838-42-5 |
| Solubility (25°C) | DMSO 100 mg/mL Ethanol 100 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
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| XL-281
XL-281 (BMS-908662) is an orally active inhibitor for RAF kinase, with IC50s of 2.6, 4.5 and 6 nM, for CRAF, B-RAF, and B-RAFV600E, respectively. |
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| Brimarafenibum
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| Belvarafenib TFA
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