Journal of Medicinal Chemistry· 2026Q1
Structure-Based Optimization of 2-Aminopyrimidine Derivatives as Potent Multi-target FLT3/CHK1/IRAK4 Inhibitors for Acute Myeloid Leukemia
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- Q1SCImago
- 2026year
Short summary
A novel 2-aminopyrimidine derivative, compound 33, acts as a potent multi-target inhibitor of FLT3, CHK1, and IRAK4, overcoming resistance mechanisms in acute myeloid leukemia (AML).
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Key points
- Compound 33 is a novel 2-aminopyrimidine derivative inhibiting FLT3, CHK1, and IRAK4.
- It shows potent activity against FLT3-WT (5.05 nM) and FLT3-D835Y (2.99 nM), CHK1 (33.32 nM), and IRAK4 (15.94 nM).
- Compound 33 overcomes cytokine-induced resistance in MV-4-11 cells and upregulates p53/p21 while downregulating PD-L1.
- In vivo studies showed significant tumor growth suppression (84.96% TGI) and prolonged survival in AML models without toxicity.
AI-generated from the title and abstract; the full text is not read.
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.
The authors' abstract, as published at the source. Journal of Medicinal Chemistry, 2026 · DOI ↗
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Field: Hematology
HematologyMedicine