侯有丽, 赵鹏娟, 刘举, 廖伟科, 汤磊. 新型FLT3抑制剂的设计、合成及活性评价J. 药学学报, 2025, 60(6): 1767-1777. DOI: 10.16438/j.0513-4870.2025-0053
引用本文: 侯有丽, 赵鹏娟, 刘举, 廖伟科, 汤磊. 新型FLT3抑制剂的设计、合成及活性评价J. 药学学报, 2025, 60(6): 1767-1777. DOI: 10.16438/j.0513-4870.2025-0053
HOU You-li, ZHAO Peng-juan, LIU Ju, LIAO Wei-ke, TANG Lei. Design, synthesis and activity evaluation of novel FLT3 inhibitorsJ. Acta Pharmaceutica Sinica, 2025, 60(6): 1767-1777. DOI: 10.16438/j.0513-4870.2025-0053
Citation: HOU You-li, ZHAO Peng-juan, LIU Ju, LIAO Wei-ke, TANG Lei. Design, synthesis and activity evaluation of novel FLT3 inhibitorsJ. Acta Pharmaceutica Sinica, 2025, 60(6): 1767-1777. DOI: 10.16438/j.0513-4870.2025-0053

新型FLT3抑制剂的设计、合成及活性评价

Design, synthesis and activity evaluation of novel FLT3 inhibitors

  • 摘要: 本研究设计并合成了一系列含咪唑-4-甲酰胺基和1,2,4-三氮唑的4-苯氧基吡啶类衍生物, 作为新型的Fms样酪氨酸激酶3 (Fms-like tyrosine kinase 3, FLT3) 抑制剂。结果表明, 该系列化合物具有良好的抗增殖活性, 其中, 优选化合物10c在含Fms样酪氨酸激酶3-内部串联重复(Fms-like tyrosine kinase 3-internal tandem duplication, FLT3-ITD) 突变的两个细胞系即人髓性单核细胞白血病细胞(MV4-11) 和人急性髓性白血病细胞(Molm-13) 的抑制生长50%所需的浓度(half maximal inhibitory concentration, IC50) 值分别为1.90和5.78 μmol·L-1。细胞凋亡和周期结果表明, 化合物10c能够促进细胞凋亡并将细胞阻止在S期。分子对接结果表明, 化合物10c与FLT3的PHE691和HIS809形成两个π-π堆积作用, 吡啶母核和Linker部分分别与FLT3的LYS644和CYS694形成重要的氢键作用。综上, 化合物10c在体外体现出较好的抗增殖活性, 具有进一步深入研究的价值, 同时也为开发出更多结构新颖的新型FLT3抑制剂奠定基础。

     

    Abstract: In this study, a series of 4-phenoxypyridine derivatives containing imidazole-4-formamido and 1,2,4-triazole were designed and synthesized as novel inhibitors of Fms-like tyrosine kinase 3 (FLT3). The results showed that the series of compounds had good antiproliferative activity. Among them, the preferred compound 10c was in two cell lines containing FLT3-ITD (internal tandem duplication, ITD) mutations, namely human myeloid core solo leukemia cells (MV4-11) and human acute myeloid leukemia cells (Molm-13), with IC50 values of 1.90 and 5.78 μmol·L-1, respectively. Apoptosis and cycle results showed that compound 10c could promote apoptosis and prevent cells in S phase. Molecular docking results showed that compound 10c formed two π-π stacking effects with PHE691 and HIS809 of FLT3, and the pyridine parent nucleus and Linker part formed important hydrogen bonds with LYS644 and CYS694 of FLT3, respectively. In summary, compound 10c exhibited good anti-proliferation activity in vitro, which is of value for further in-depth research, and also lays the foundation for the development of more novel FLT3 inhibitors with novel structures.

     

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