Discovery of 3-amide-pyrimidine-based derivatives as potential fms-like tyrosine receptor kinase 3 (FLT3) inhibitors for treating acute myelogenous leukemia

IF 2.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Bioorganic & Medicinal Chemistry Letters Pub Date : 2024-12-19 DOI:10.1016/j.bmcl.2024.130082

Wei Liu , Yi Ma , Miaomiao Wang , Youyou He , Yanhong Liu , Zhenbao Zhu , Yi Ding , Ge Zhang , Shengzheng Wang

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Abstract

FLT3-ITD and TKD mutants play a central role in acute myeloid leukemia (AML), making FLT3 an attractive target for AML treatment. To discover next-generation FLT3 inhibitors and gather additional structure–activity relationship (SAR) information, we performed structural modifications of G-749 (denfivontinib) utilizing structure simplification and scaffold hopping strategies. Among these derivatives, MY-10 exhibited the most potent and selective inhibition of MV4-11 cell proliferation, demonstrating potent inhibitory activity against FLT3-ITD (IC₅₀ = 6.5 nM) and FLT3-D835Y (IC₅₀ = 10.3 nM) mutants. Notably, MY-10 exhibited no inhibitory activity against c-KIT kinase (IC₅₀ > 100 μM). Mechanistic studies revealed that MY-10 arrested the cell cycle at the G0/G1 phase and efficiently induced apoptosis. Furthermore, it significantly reduced reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP), and strongly inhibited FLT3-mediated signaling pathways. These findings, along with the obtained SAR information, provide valuable insights for the further development of FLT3 inhibitors.

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发现基于3-酰胺嘧啶的衍生物作为治疗急性髓性白血病的潜在fms样酪氨酸受体激酶3 （FLT3）抑制剂。

FLT3- itd和TKD突变体在急性髓性白血病（AML）中发挥核心作用，使FLT3成为AML治疗的一个有吸引力的靶点。为了发现下一代FLT3抑制剂并收集额外的构效关系（SAR）信息，我们利用结构简化和支架跳跃策略对G-749 （denfivontinib）进行了结构修饰。在这些衍生物中，mi -10对MV4-11细胞增殖表现出最有效和选择性的抑制作用，对FLT3-ITD （IC50 = 6.5 nM）和FLT3-D835Y （IC50 = 10.3 nM）突变体表现出有效的抑制活性。值得注意的是，MY-10对c-KIT激酶没有抑制活性（IC50 > 100 μM）。机制研究表明，MY-10在G0/G1期阻滞细胞周期，有效诱导细胞凋亡。此外，它显著降低活性氧（ROS）的产生和线粒体膜电位（MMP），并强烈抑制flt3介导的信号通路。这些发现，以及获得的SAR信息，为进一步开发FLT3抑制剂提供了有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bioorganic & Medicinal Chemistry Letters 医学-医药化学

CiteScore

5.70

自引率

3.70%

发文量

463

审稿时长

27 days

期刊介绍： Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.