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通过支架跳跃发现的新型咪唑并[1,2-]哒嗪衍生物抑制急性髓系白血病中的 FLT3-ITD 激酶。

Inhibition of FLT3-ITD Kinase in Acute Myeloid Leukemia by New Imidazo[1,2-]pyridazine Derivatives Identified by Scaffold Hopping.

机构信息

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo nám. 2, 16000 Prague, Czech Republic.

Department of Experimental Biology, Faculty of Science, Palacký University Olomouc, Šlechtitelů 27, 78371 Olomouc, Czech Republic.

出版信息

J Med Chem. 2023 Aug 24;66(16):11133-11157. doi: 10.1021/acs.jmedchem.3c00575. Epub 2023 Aug 3.

DOI:10.1021/acs.jmedchem.3c00575
PMID:37535845
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10461230/
Abstract

FLT3 kinase is a potential drug target in acute myeloid leukemia (AML). Patients with FLT3 mutations typically have higher relapse rates and worse outcomes than patients without FLT3 mutations. In this study, we investigated the suitability of various heterocycles as central cores of FLT3 inhibitors, including thieno[3,2-]pyrimidine, pyrazolo[1,5-]pyrimidine, imidazo[4,5-]pyridine, pyrido[4,3-]pyrimidine, and imidazo[1,2-]pyridazine. Our assays revealed a series of imidazo[1,2-]pyridazines with high potency against FLT3. Compound showed nanomolar inhibitory activity against recombinant FLT3-ITD and FLT3-D835Y (IC values 4 and 1 nM, respectively) as well as in the FLT3-ITD-positive AML cell lines MV4-11, MOLM-13, and MOLM-13 expressing the FLT3-ITD-D835Y mutant (GI values of 7, 9, and 4 nM, respectively). In contrast, FLT3-independent cell lines were much less sensitive. In vitro experiments confirmed suppression of FLT3 downstream signaling pathways. Finally, the treatment of MV4-11 xenograft-bearing mice with at doses of 5 and 10 mg/kg markedly blocked tumor growth without any adverse effects.

摘要

FLT3 激酶是急性髓细胞白血病（AML）的潜在药物靶点。携带 FLT3 突变的患者通常比没有 FLT3 突变的患者复发率更高，预后更差。在这项研究中，我们研究了各种杂环作为 FLT3 抑制剂的中心核心的适用性，包括噻吩并[3,2-d]嘧啶、吡唑并[1,5-d]嘧啶、咪唑并[4,5-d]吡啶、吡啶并[4,3-d]嘧啶和咪唑并[1,2-a]哒嗪。我们的测定结果显示了一系列具有高活性的咪唑并[1,2-a]哒嗪类化合物对 FLT3 的抑制作用。化合物对重组 FLT3-ITD 和 FLT3-D835Y 具有纳摩尔抑制活性（IC 值分别为 4 和 1 nM），对表达 FLT3-ITD-D835Y 突变体的 FLT3-ITD 阳性 AML 细胞系 MV4-11、MOLM-13 和 MOLM-13 也具有抑制活性（GI 值分别为 7、9 和 4 nM）。相比之下，FLT3 非依赖性细胞系的敏感性要低得多。体外实验证实了对 FLT3 下游信号通路的抑制作用。最后，用 以 5 和 10 mg/kg 的剂量治疗 MV4-11 异种移植荷瘤小鼠显著抑制了肿瘤生长，没有任何不良反应。

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