由于后天性和适应性耐药性以及与人类乙烯基-a-去伐骨的基因（hERG）通道阻断有关的心脏毒性，FLT3抑制剂作为单一药物的效果有限，这进一步阻碍了安全药物的上市。需要具有克服耐药性并降低hERG亲和力的抑制剂。在这里，我们报道了一种双重FLT3/CHK1抑制剂18，它在FLT3-TKD和FLT3-ITD-TKD突变的BaF3细胞中表现出对不同后天获得性耐药性的优势。此外，18对c-KIT的选择性超过1700倍，并且大大降低了hERG的亲和力，IC50值为58.4 μM。进一步的机制研究表明，18能够上调p53并抑制适应性耐药细胞的生长。在体内研究中，18表现出有利的药代动力学特性和良好的安全性，在MV-4-11细胞接种的小鼠异种移植模型中抑制了肿瘤生长，并在Molm-13移植模型中延长了生存时间，支持其进一步开发。

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.