Identification of 1,3-thiazinan-4-one urea-based derivatives as potent FLT3/VEGFR2 dual inhibitors for the treatment of acute myeloid leukemia

Abstract

Blockage of multiple oncoprotein or pathway is a more effective approach in current cancer therapy. In this investigation, structural modification was performed on a lead compound, N1-(2,4-difluoro-phenyl)-N3-(2-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-oxothiazolidin-3-yl)urea (BMC-17b), which was obtained in our previous study and showed potent inhibitory activities against FLT3 and VEGFR2. Nine novel derivatives were synthesized, and structure-activity relationships (SARs) analysis based on the biological evaluation and docking study led to the discovery of several more potent FLT3/VEGFR2 dual inhibitors. Among them, 1-(2-(3-fluoro-4-((6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinolin-4-yl)oxy)phenyl)-4-oxo-1,3-thiazinan-3-yl)-3-phenylurea (4f) possessed significantly inhibitory activities against FLT3, VEGFR2 and FLT3-driven AML MV4-11 cells with IC50 values of 6.9 nM, 14.6 nM and 12.1 nM, respectively. Furthermore, compound 4f exhibited over 41-fold selectivity toward FLT3 relative to c-Kit, which might reduce myelosuppression toxicity.