一种新型高效JAK2抑制剂治疗三阴性乳腺癌的发现和生物学评价。

IF 5.4 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Enzyme Inhibition and Medicinal Chemistry Pub Date : 2025-12-01 Epub Date: 2025-04-29 DOI:10.1080/14756366.2025.2488127

Yingxiang Miao, Shudan Yang, Fang Zhang, Jindong Li, Yan Zhang

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引用次数: 0

摘要

Janus激酶2 （JAK2）被认为是治疗三阴性乳腺癌（TNBC）的一个有吸引力的靶点。在此，我们利用基于结构的虚拟筛选和分子对接发现了6种JAK2抑制剂。其中，JNN-5为最佳化合物。在纳米摩尔范围内对JAK2有较强的抑制作用（IC50 = 0.41±0.03 nM），对JAK1和JAK3具有较高的选择性（选择性指数（SI） bb0 73.17）。此外，分子动力学（MD）模拟表明，JNN-5与JAK2 JH1的结合具有很高的稳定性。细胞实验显示，JNN-5在TNBC细胞系（MDA-MB-468、MDA-MB-213、HCC70、MDA-MB-157）中表现出较强的抗增殖活性。JNN-5显著降低HUVECs的迁移，且呈剂量依赖性。JNN-5对多药耐药MDA-MB-231/ADR有显著抑制作用（IC50 = 0.37±0.02 μM）。这些数据表明，JNN-5可能是一种治疗TNBC的高效选择性抗肿瘤化合物。

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Discovery and biological evaluation of a novel and highly potent JAK2 inhibitor for the treatment of triple negative breast cancer.

Janus kinase 2 (JAK2) is considered an attractive target for the treatment of triple-negative breast cancer (TNBC). Herein, we discovered six JAK2 inhibitors using structure-based virtual screening and molecular docking. Among them, JNN-5 was the best compound. It indicated strong inhibitory effects on JAK2 in the nanomolar range (IC₅₀ = 0.41 ± 0.03 nM), and high selectivity for JAK2 over JAK1 and JAK3 (selectivity index (SI) > 73.17). Moreover, molecular dynamics (MD) simulation exhibited that JNN-5 bound with high stability to JAK2 JH1. Cellular assays revealed that JNN-5 displayed strong antiproliferative activities in the TNBC cell lines (MDA-MB-468, MDA-MB-213, HCC70, MDA-MB-157). JNN-5 significantly reduced the migration of HUVECs with the dose-dependence. JNN-5 had a significant inhibitory effect on multidrug-resistant MDA-MB-231/ADR (IC₅₀ = 0.37 ± 0.02 μM). These data demonstrate that JNN-5 may be a highly effective and selective antitumor compound for the treatment of TNBC.

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来源期刊

Journal of Enzyme Inhibition and Medicinal Chemistry 医学-生化与分子生物学

CiteScore

10.30

自引率

10.70%

发文量

195

审稿时长

4-8 weeks

期刊介绍： Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.