Miao Yingxiang, Yang Shudan, Zhang Fang, Li Jindong, Zhang Yan
Department of Pharmacy, Affiliated Nantong Hospital 3 of Nantong University, Nantong Third People's Hospital, Nantong, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
J Enzyme Inhib Med Chem. 2025 Dec;40(1):2488127. doi: 10.1080/14756366.2025.2488127. Epub 2025 Apr 29.
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 (IC = 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 (IC = 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.
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，我们通过基于结构的虚拟筛选和分子对接发现了六种JAK2抑制剂。其中，JNN-5是最佳化合物。它在纳摩尔范围内对JAK2表现出强烈的抑制作用（IC = 0.41±0.03 nM），并且对JAK2的选择性高于JAK1和JAK3（选择性指数（SI）> 73.17）。此外，分子动力学（MD）模拟显示JNN-5与JAK2 JH1具有高稳定性结合。细胞实验表明，JNN-5在TNBC细胞系（MDA-MB-468、MDA-MB-213、HCC70、MDA-MB-157）中表现出强烈的抗增殖活性。JNN-5以剂量依赖性显著降低人脐静脉内皮细胞（HUVECs）的迁移。JNN-5对多药耐药的MDA-MB-231/ADR具有显著抑制作用（IC = 0.37±0.02 μM）。这些数据表明，JNN-5可能是一种治疗TNBC的高效且选择性的抗肿瘤化合物。
