1370466-81-1

FLT3/BTK.

In FLT3-ITD AML cells, CG-806 induces apoptosis through inhibition of FLT3 signaling (decreases phospho-FLT3, -STAT5 and -ERK) and promotion of G0/G1 cell cycle arrest. In FLT3-WT AML cell lines, or Ba/F3 cells transfected with FLT3-WT, D835Y, ITD+D835Y, or ITD+F691L, CG-806 markedly decreases phosphorylation of BTK, aurora kinases (AURK) and H3S10, resulting in G2/M arrest or polyploidy, and apoptosis with less or no effect on FLT3-WT activity. CG-806 decreases BTK phosphorylation in all malignant B cell lines tested and inhibits cell proliferation and colony formation.CG-806 equivalently inhibits BTK-WT and BTK-C481S in HEK293 transfected cells.

CG-806 (0-120 mg/kg; oral administration; for 28 days; CD-1 mice) treatment suppresses leukemia growth at all doses tested throughout the 28-day period of dosing, and has no adverse CG-806-related effects on body weight, ophthalmic, respiratory or neurological examinations, clinical pathology (coagulation, clinical chemistry, or urinalysis), organ weight or macroscopic evaluations in the subcutaneous MV4-11 xenograft model.