839706-07-9

GNF-7 inhibits Bcr-Abl WT and Bcr-Abl T315I with IC50 of 133 nM and 61 nM, respectively. IC50 value: 133 nM (Bcr-Abl WT), 61 nM (Bcr-Abl T315I)Target: Bcr-Ablin vitro: GNF-7 is amongst the first type II inhibitors capable of inhibiting T315I to be described and will serve as a valuable lead to design next generation Bcr-Abl kinase inhibitors. GNF-7 exhibits some selectivity (4 to 100-fold) for T315I Bcr-Abl (IC50 = 11 nM, in Ba/F3 cell line) relative to kinases such as TPR-Met, NPM-ALK, JAK-3, Flt-3. in vivo: GNF-7 displays significant efficacy against T315I-Bcr-Abl without appreciable toxicity in a bioluminescent xenograft mouse model using a transformed T315I-Bcr-Abl-Ba/F3 cell line that has a stable luciferase expression. GNF-7 exhibits excellent pharmacokinetic parameters in mice, with good systemic exposure (AUC = 26656 hrs*nM, Cmax = 3.6 uM) along with reasonable half life (t1/2=3.2 hrs) and favorable oral bioavailability (BAV=36%) being observed following oral administration of a single dose of 20 mg/kg.