Discovery of a highly selective FLT3 kinase inhibitor from phenotypic cell viability profiling

Abstract

We discovered a novel molecular framework 4 containing a heterobiaryl pyrazolopyridine moiety as a selective FLT3 kinase inhibitor from phenotype-based viability profiling. Compound 4g showed outstanding selectivity in cellular cytotoxicity against MV-4-11 leukemic cells via the induction of apoptosis. The hypothesis-driven deconvolution elucidated that compound 4g selectively blocked the phosphorylation of FLT3 and its downstream effectors, such as ERK and STAT5, only in MV-4-11 cells. The inhibitory effect of 4g on in vitro enzyme function and FLT3 phosphorylation in cells proved that FLT3 kinase is a direct molecular target of 4g. Finally, the kinase activity profiling of 4g verified its excellent selectivity toward FLT3 over 40 representative kinases, including the receptor tyrosine kinase (RTK) family.