Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

Secondary
mutations of FLT3 have become the main mechanism of FLT3
inhibitor resistance that presents a significant clinical challenge.
Herein, a series of pyrazole-3-amine derivatives were synthesized
and optimized to overcome the common secondary resistance mutations
of FLT3. The structure–activity relationship and molecular
dynamics simulation studies illustrated that the ribose region of
FLT3 could be occupied to help address the obstacle of secondary mutations.
Among those derivatives, compound 67 exhibited potent
and selective inhibitory activities against FLT3-ITD-positive acute
myeloid leukemia (AML) cells and possessed equivalent potency against
transformed BaF3 cells with a variety of secondary mutations. Besides,
cellular mechanism assays demonstrated that 67 strongly
inhibited phosphorylation of FLT3 and its downstream signaling factors,
as well as induced cell cycle arrest and apoptosis in MV4-11 cells.
In the MV4-11 xenograft models, 67 exhibited potent antitumor
potency without obvious toxicity. Taken together, these results demonstrated
that 67 might be a drug candidate for the treatment of
FLT3-ITD-positive AML.