Discovery of novel aminopyrimidine-hydroxamate derivatives as dual FLT3/HDAC inhibitors: Design, synthesis, and anti-hematologic malignancy evaluation.

The constitutive activation of FMS-like tyrosine kinase 3 (FLT3) is closely associated with the progression of hematologic malignancies; however, the clinical application of FLT3 inhibitors has been limited by acquired drug resistance. Recent advances in epigenetic regulatory mechanisms revealed that aberrant histone deacetylase (HDAC) expression exacerbates resistance to FLT3 inhibitors through multiple signaling pathways. Accordingly, we designed and synthesized a series of aminopyrimidine-hydroxamate derivatives (6a-6s) as dual FLT3/HDAC inhibitors for the treatment of hematologic malignancies. The representative compound 6s demonstrates superior dual-targeting properties, exhibiting 150-fold higher FLT3 inhibition (half-maximal inhibitory concentration (IC50) = 14 nM) compared with the reference drug tandutinib (IC50 = 2098 nM) and 2.9-fold higher HDAC1 inhibition (IC50 = 27 nM) relative to vorinostat (SAHA; IC50 = 79 nM). In the human acute myeloid leukemia MV-4-11 cell line, 6s exhibits remarkable antiproliferative potency (IC50 = 29 nM), outperforming the single-target inhibitors tandutinib (IC50 = 7630 nM) and SAHA (IC50 = 3760 nM) by 263- and 129-folds, respectively. Notably, 6s shows marked efficacy in a human mantle cell lymphoma Jeko-1 model (IC50 = 99 nM), indicating broad-spectrum therapeutic potential. Furthermore, 6s exhibits remarkable kinase selectivity, plasma stability, and human hepatic microsomal metabolic stability. Importantly, in the Jeko-1 xenograft model, 6s achieves 53.34 % tumor growth inhibition at a dose of 30 mg/kg with no observable toxicity. Collectively, these results indicate that 6s is a potent dual FLT3/HDAC inhibitor with promising therapeutic potential for hematologic malignancies.