Simultaneous inhibition of FLT3 and HDAC by novel 6-ethylpyrazine-2-Carboxamide derivatives provides therapeutic advantages in acute myelocytic leukemia,European Journal of Medicinal Chemistry

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Simultaneous inhibition of FLT3 and HDAC by novel 6-ethylpyrazine-2-Carboxamide derivatives provides therapeutic advantages in acute myelocytic leukemia
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-09-06 , DOI: 10.1016/j.ejmech.2024.116847
Yingjie Chang ₁ , Xue Li ₁ , Yue Zhou ₂ , Xinying Yang ₁ , Wei Zhao ₂ , Hao Fang ₁ , Xuben Hou ₁

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Synergetic inhibition of FMS-like tyrosine kinase 3 (FLT3) and histone deacetylase (HDAC) by small molecule chimera presents a promising therapeutic approach for acute myeloid leukemia (AML) with FLT3 mutations. In this study, we first observed that the combined use of FLT3 inhibitor gilteritinib and HDAC inhibitor vorinostat increased the survival rate of leukemia xenograft mouse model. Then, we employed a pharmacophore fusion strategy to develop a novel series of FLT3/HDAC dual inhibitors. Among them, compound 25h demonstrated superior inhibitory activity against both FLT3 and HDAC. In particular, compound 25h exhibited enhanced anti-proliferation activity against MOLM-13 cells in comparison to gilteritinib, vorinostat, and their combination, while maintaining reduced cytotoxicity towards normal cells. Mechanistically, the heightened anti-tumor effect of compound 25h was attributed to its more potent regulation of intracellular pathways, notably phosphorylation of ERK, compared to single drug and combination treatments. Furthermore, compound 25h demonstrated superior anti-tumor efficacy in the MOLM-13 xenograft model compared to combination therapy, along with reduced in vivo toxicity. To conclude, we have identified a novel FLT3/HDAC dual inhibitor that could serve as a potential candidate for the treatment of AML.

中文翻译：

新型 6-乙基吡嗪-2-羧酰胺衍生物同时抑制 FLT3 和 HDAC 为急性粒细胞白血病提供了治疗优势

小分子嵌合体对 FMS 样酪氨酸激酶 3 （FLT3）和组蛋白脱乙酰酶（HDAC）的协同抑制为具有 FLT3 突变的急性髓性白血病（AML）提供了一种有前途的治疗方法。在这项研究中，我们首先观察到 FLT3 抑制剂吉替替尼和 HDAC 抑制剂伏立诺他联合使用提高了白血病异种移植小鼠模型的存活率。然后，我们采用药效团融合策略开发了一系列新型 FLT3/HDAC 双重抑制剂。其中，化合物 25h 对 FLT3 和 HDAC 均表现出优异的抑制活性。特别是，与吉替替尼、伏立诺他及其组合相比，化合物 25h 对 MOLM-13 细胞表现出增强的抗增殖活性，同时保持对正常细胞的细胞毒性降低。从机制上讲，化合物 25h 的抗肿瘤作用增强归因于与单一药物和联合治疗相比，它对细胞内途径的调节更有效，特别是 ERK 的磷酸化。此外，与联合治疗相比，化合物 25h 在 MOLM-13 异种移植模型中表现出优异的抗肿瘤疗效，同时降低体内毒性。总而言之，我们已经确定了一种新型 FLT3/HDAC 双重抑制剂，可以作为治疗 AML 的潜在候选药物。

更新日期：2024-09-06

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