| Identification | Back Directory | [Name]
RAF709 | [CAS]
1628838-42-5 | [Synonyms]
RAF709
CS-2505
RAF-709;RAF 709
N-[2-Methyl-5'-(4-morpholinyl)-6'-[(tetrahydro-2H-pyran-4-yl)oxy][3,3'-bipyridin]-5-yl]-3-(trifluoromethyl)benzamide
Benzamide, N-[2-methyl-5'-(4-morpholinyl)-6'-[(tetrahydro-2H-pyran-4-yl)oxy][3,3'-bipyridin]-5-yl]-3-(trifluoromethyl)- | [Molecular Formula]
C28H29F3N4O4 | [MDL Number]
MFCD30534393 | [MOL File]
1628838-42-5.mol | [Molecular Weight]
542.55 |
| Chemical Properties | Back Directory | [Boiling point ]
622.7±55.0 °C(Predicted) | [density ]
1.321±0.06 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
DMSO:100.0(Max Conc. mg/mL);184.31(Max Conc. mM)
DMSO:PBS (pH 7.2) (1:2):0.33(Max Conc. mg/mL);0.61(Max Conc. mM)
DMF:30.0(Max Conc. mg/mL);55.29(Max Conc. mM)
Ethanol:100.0(Max Conc. mg/mL);184.31(Max Conc. mM) | [form ]
A crystalline solid | [pka]
11.87±0.70(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Description]
RAF709 is a potent inhibitor of B-RAF and C-RAF (IC50s = 0.4 and 0.5 nM, respectively).1 It is selective for RAF kinases exhibiting >99% inhibition of only B-RAF, B-RAFV600E, and C-RAF in a panel of 456 kinases. However, DDR1, DDR2, FRK, and PDGFRβ are also inhibited by >80% at a concentration of 1 μM. RAF709 inhibits phosphorylation of MEK and ERK (EC50s = 0.02 and 0.1 μM, respectively) with minimal paradoxical activation, stabilizes BRAF-CRAF dimers (EC50 = 0.8 μM), and reduces proliferation of Calu-6 RAS mutant cells (EC50 = 0.95 μM). In a Calu-6 mouse non-small cell lung cancer (NSCLC) xenograft model, RAF709 (10-200 mg/kg) reduces ERK phosphorylation and decreases tumor volume in a dose-dependent manner without affecting total body weight. | [Uses]
RAF709 is a potent, selective, and efficacious RAF inhibitor with IC50s of 0.4 nM and 0.5 nM for BRAF and CRAF, respectively[1]. Antitumor efficacy[1]. | [in vivo]
RAF709 proves to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model. RAF709 shows dose-proportional increases in plasma exposure and a corresponding dosedependent inhibition of pERK in Calu-6 tumors. Treatment with RAF709 results in dose-dependent antitumor activity with 10 mg/kg being subefficacious (%T/C=92%), 30 mg/kg results in measurable antitumor activity (%T/C=46%), and 200 mg/kg results in mean tumor regression of 92%, while the same high dose is not efficacious in the PC3, KRAS WT model[1]. | [IC 50]
CRAF: 0.5 nM (IC50); Braf: 0.4 nM (IC50) | [References]
[1] Nishiguchi GA, et al. 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. J Med Chem. 2017 Jun 22;60(12):4869-4881. DOI:10.1021/acs.jmedchem.6b01862 |
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