GNF-2

GNF-2 is a highly selective non-ATP competitive inhibitor of oncogenic Bcr-Abl activity (IC50 = 0.14 μM).IC50 value: 0.14 uM [1]Target: Bcr-Ablin vitro: Ba/F3 cells harboring native or T315I mutated Bcr-Abl constructs were treated with GNF-2 and AKIs. We monitored the effect of GNF-2 with AKIs on the proliferation and clonigenicity of the different Ba/F3 cells. In addition, we monitored the auto-phosphorylation activity of Bcr-Abl and JAK2 in cells treated with GNF-2 and AKIs [2]. GNF-2

3-[6-(4-Trifluoromethoxy-phenylamino)-pyrimidin-4-yl]-benzamide (GNF-2) 4, 6-dichloropyrimidine (1 g, 6.7 mmol) is dissolved with p-trifluoromethoxy aniline (1.2 g, 6.7 mmol) in 15 mL ethanol, then 1.75 mL DIEA (10 mmol) is added. Reaction is under reflux for 2 hours, and cooled down to room temperature. After evaporating the solvent, the crude product is purified by flash chromatography (EA/Hexane=3:7) to give (6-chloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine as a white solid. To a degassed solution of (6-chloropyrimidin-4-yl)-(4-trifluoromethoxyphenyl)-amine (73 mg, 0.25 mmol) and (3-aminocarbonylphenyl)-boronic acid (42 mg, 0.25 mmol) in 0.4 M sodium carbonate aqueous solution (1.3 mL) and acetonitrile (1.3 mL) is added PPh3 (15 mg, 0.01 mmol). After stirring at about 90 C. under N2 for 12 hours, the reaction mixture is partitioned between saturated NaHCO3 and CHCl3/2-propanol (4:1). The aqueous layer is extracted with additional CHCl3/2-propanol (4:1) and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The resultant yellowish oil is purified by column chromatography (SiO2, ethyl acetate) to give 3-[6-(4-trifluoromethoxyphenyl-amino)-pyrimidin-4-yl]-benzamide as a white solid. MSm/z 375.10(M+1).