Resistance to FMS-like tyrosine kinase 3 (FLT3) inhibitors in acute myeloid leukemia (AML) challenges their clinical efficacy. Such resistance is frequently mediated by the overexpression of histone deacetylase 8 (HDAC8), and provide a rational for the dual targeting of both FLT3 and HDAC8. Here we describe the design and synthesis of new dual inhibitors that incorporate a thienopyrimidine pharmacophore for FLT3, the hydroxamic acid zinc binding group for HDAC8 and a metabolically stable pyridone linker. Compound A5452, however, had only slight inhibitory activity against wild type and the D835Y mutant FLT3 (IC50> 10,000 nM). Further efforts will include the structure-based optimization based on the computational modeling to improve the potency, particularly by introducing substituents on the C5 position of the thienopyrimidine core for the development of potent FLT3-HDAC8 dual inhibitors for AML treatment.