Discovery of pyrrolo[2,3-d]pyrimidine derivatives as novel FLT3/IRAK4 inhibitors

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-06-13 DOI:10.1016/j.ejmech.2025.117845

Haibin Yuan , Yue Gao , Peipei Wang , Xiaowu Dong , Jia Li , Chenxi Wang , Jinxin Che , Yubo Zhou , Tao Liu

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Abstract

Starting with the lead compound L-1, a series of pyrrolo[2,3-d]pyrimidine derivatives were developed as FLT3/IRAK4 inhibitors through three rounds of rational structural optimization. Among them, HB-29 had the remarkable activity towards FLT3-WT (IC₅₀ = 1.95 nM) and IRAK4 (IC₅₀ = 53.72 nM), outperforming the positive control, CA-4948. Besides, it exhibited excellent activities in MV4-11, MOLM3, and BaF3 cells with varying FLT3-TKD and FLT3-ITD-TKD mutations, highlighting its potential to overcome acquired resistance. The toxicity of HB-29 to normal bone marrow cell line HS-5 is relatively low (SI > 2000). Mechanistic studies revealed that HB-29 inhibited FLT3 and IRAK4 pathways in a dose-dependent manner, promoting cell apoptosis. Notably, in the cytokine-induced cell model, HB-29 efficiently induced apoptosis, and while also enhancing SOD activity and reducing ROS accumulation, thereby demonstrating its potential to overcome adaptive resistance. Moreover, HB-29 demonstrated an acceptable bioavailability (F = 13.4 %). These findings confirm that FLT3/IRAK4 inhibitor is a promising strategy for the treatment of AML.

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吡咯[2,3-d]嘧啶衍生物作为新型FLT3/IRAK4抑制剂的发现

从先导化合物L-1开始，经过三轮合理的结构优化，开发出一系列吡咯[2,3-d]嘧啶衍生物作为FLT3/IRAK4抑制剂。其中HB-29对FLT3-WT （IC50 = 1.95 nM）和IRAK4 （IC50 = 53.72 nM）的活性显著高于阳性对照CA-4948。此外，它在具有不同FLT3-TKD和FLT3-ITD-TKD突变的MV4-11、MOLM3和BaF3细胞中表现出优异的活性，突出了其克服获得性耐药的潜力。HB-29对正常骨髓细胞系HS-5的毒性较低(SI >；2000)。机制研究显示HB-29以剂量依赖的方式抑制FLT3和IRAK4通路，促进细胞凋亡。值得注意的是，在细胞因子诱导的细胞模型中，HB-29有效地诱导细胞凋亡，同时还能增强SOD活性，减少ROS积累，从而显示出其克服适应性抗性的潜力。此外，HB-29表现出可接受的生物利用度（F = 13.4%）。这些发现证实FLT3/IRAK4抑制剂是一种治疗AML的有希望的策略。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.