Discovery of 2‑Aminopyrimidine Derivatives as Potent Dual FLT3/CHK1 Inhibitors with Significantly Reduced hERG Inhibitory Activities

FLT3 inhibitors as single agents have limited effects
because of
acquired and adaptive resistance and the cardiotoxicity related to
human ether-a-go-go-related gene (hERG) channel blockade further impedes
safe drugs to the market. Inhibitors having potential to overcome
resistance and reduce hERG affinity are highly demanded. Here, we
reported a dual FLT3/CHK1 inhibitor 18, which displayed
potencies to overcome varying acquired resistance in BaF3 cells with
FLT3-TKD and FLT3-ITD-TKD mutations. Moreover, 18 displayed
high selectivity over c-KIT more than 1700-fold and greatly reduced
hERG affinity, with an IC50 value of 58.4 μM. Further
mechanistic studies demonstrated 18 can upregulate p53
and abolish the outgrowth of adaptive resistant cells. In the in vivo
studies, 18 demonstrated favorable PK profiles and good
safety, suppressed the tumor growth in the MV-4–11 cell inoculated
mouse xenograft model, and prolonged the survival in the Molm-13 transplantation
model, supporting its further development.