Structure-Based Optimization of 2-Aminopyrimidine Derivatives as Potent Multi-target FLT3/CHK1/IRAK4 Inhibitors for Acute Myeloid Leukemia

Abstract

Abstract The efficacy of FLT3 inhibitors is limited by resistance. Co-inhibiting FLT3 and CHK1 can overcome FLT3i resistance, and IRAK4 signaling contributes to leukemic cell survival in FLT3-mutant acute myeloid leukemia (AML). We discovered a novel series of 2-aminopyrimidine derivatives as potent multi-target FLT3/CHK1/IRAK4 inhibitors. Among them, compound 33 exhibited potent activity against FLT3-WT (IC50 = 5.05 nM), FLT3-D835Y (IC50 = 2.99 nM), CHK1 (IC50 = 33.32 nM), and IRAK4 (IC50 = 15.94 nM), with 85-fold selectivity over c-KIT. Moreover, it potently inhibited FLT3-mutant BaF3 cells and blocked FLT3/CHK1/IRAK4 signaling, upregulating p53/p21 and downregulating PD-L1. It overcame cytokine-induced resistance in MV-4-11 cells. In vivo, 33 significantly suppressed tumor growth in MV-4-11 xenografts (TGI = 84.96% at 5 mg/kg) and prolonged survival (from 40.5 days to 61.5 days) in a disseminated AML model without toxicity. These results demonstrate that 33 is a promising multi-target inhibitor candidate for FLT3-mutant AML.