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

Abstract

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.