GNE-9815 (C09-1134-775)

GNE-9815 (compound 7) is a highly selective, pan- RAF inhibitor with good oral bioavailability. GNE-9815 exhibits K i values of 0.062 and 0.19 nM for CRAF and BRAF , respectively. GNE-9815 combines with MEK inhibitor Cobimetinib ( HY-13064 ) shows synergistic modulation of MAPK pathway. GNE-9815 can be used in studies of KRAS mutant cancersIn VitroGNE-9815 shows synergistic activity in KRAS mutant A549 and HCT116 cancer cells in combination with the MEK inhibitor Cobimetinib. MCE has not independently confirmed the accuracy of these methods. They are for reference only.In VivoGNE-9815 (15 mg/kg; p.o.; single) demonstrates synergistic MAPK pathway modulation when combines with the MEK inhibitor Cobimetinib in an HCT116 xenograft mouse model . GNE-9815 (5 mg/kg; p.o.; single) shows good oral bioavailability and (1 mg/kg; i.v.; single) exhibits low blood clearance, moderate volume of distribution, and short half-life . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: Female NCR nude mice (6 to 8-week-old; 24-26 g; HCT116 xenograft mice model) . Dosage: 15 mg/kg Administration: Intravenous injection or oral administration; single. Result: Resulted in pathway inhibition as demonstrated by partial inhibition of pRSK between 2 and 24 h, but more robust, albeit transient, inhibition of the downstream MAPK target genes, DUSP6 and SPRY4. Led to deeper inhibition of the downstream MAPK target genes DUSP6 and SPRY4, when combined with the MEK inhibitor Cobimetinib, with maximal inhibition at 8 h and with a more modest rebound in levels at 24 h, post final dose. Animal Model: Female NCR nude mice (6 to 8-week-old; 24-26 g) . Dosage: 1 mg/kg (for i.v.); 5 mg/kg (for p.o.). Administration: Intravenous injection or oral administration; single. Result: Exhibited CL b , V dss and t 1/2 values of 17 mL/min∙kg, 1.7 L/kg and 1.9 h, respectively. Showed good oral bioavailability with F% of 37%. (methylcellulose/Tween formulation).Form:SolidIC50& Target:CRAF 0.062 nM (Ki) Braf 0.19 nM (Ki). Specification: 0.98 Molecular Formula: C26H22FN5O2 Molecular Weight: 455.48