Design, Synthesis, and Biological Evaluation of Potent FLT3 Inhibitor for Acute Myeloid Leukemia (AML) Treatment

Acute myeloid leukemia (AML) is a clonal malignant proliferative disease of myeloid progenitor cells in the hematopoietic system, with a lower than 5-year overall survival rate. At present, three FLT3 inhibitors have been approved, but these drugs are prone to cause resistance after a period of medication. Developing new FLT3 inhibitors with novel structures is an effective strategy to enhance drug treatment efficacy. This study presents an extension of our effort to design and synthesize a series of novel pyrimidine-2,4-diamine derivatives as inhibitors of FLT3. The most active compound, 7r, showed significant inhibition against FLT3 with IC₅₀ value of 7.82 nM. In addition, 7r exhibited prominent anticancer activities against AML cell lines, such as MV4-11 (IC₅₀ = 46.07 nM) and MOLM-13 (IC₅₀ = 51.6 nM). Compound 7r inhibited phosphorylation of FLT3 pathways in a dose-dependent manner in MV4-11 cell lines.