Identification of 2‑Aminopyrimidine Derivatives as FLT3 Kinase Inhibitors with High Selectivity over c‑KIT

Herein, we report two promising compounds 30 and 36 possessing nanomolar FLT3 inhibitory
activities (IC50 = 1.5–7.2 nM), high selectivity
over c-KIT (>1000-fold),
and excellent anti-AML activity (MV4-11 IC50 = 0.8–3.2
nM). Furthermore, these two compounds efficiently inhibited the growth
of multiple mutant BaF3 cells expressing FLT3-ITD, FLT3-D835V/F, FLT3-F691L,
FLT3-ITD-F691L, and FLT3-ITD-D835Y. Oral administration of 30 and 36 at 6 mg/kg/d could significantly suppress tumor
growth in the MV4-11 cell-inoculated xenograft model, exhibiting tumor
growth inhibitory rates of 83.5% and 95.1%, respectively. Importantly, 36 could prolong the mouse survival time in the FLT3-ITD-TKD
dual mutation syngeneic mouse model (BaF3-FLT3-ITD-D835Y) at a dose
of 6 mg/kg p.o. bid/4W. No clear myelosuppression was observed in
the treated group of 36 in the MPO strain of zebrafish,
even at 10 μM. In summary, our data demonstrated that 36 may represent a promising candidate for the treatment of
FLT3 mutant AML.