Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
MOE Key Laboratory of Green Chemistry and Technology, College of Chemistry, Sichuan University, Chengdu, Sichuan 610064, China.
Bioorg Chem. 2023 Mar;132:106386. doi: 10.1016/j.bioorg.2023.106386. Epub 2023 Jan 21.
Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9H-purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively. The western blot assay demonstrated that 9j performed good functional potency in the NF-κB pathway and the phosphorylation of p65, IκB-α, and IKKα/β signal intensities were suppressed on RAW264.7 cell lines. Furthermore, 9j significantly improved the disease symptoms in a Ba/F3-JAK2 allograft model. Meanwhile, 9j was also effective in relieving symptoms in an acute ulcerative colitis model. Taken together, 9j was a potent JAK2/BRD4(BD2) dual target inhibitor and could be a potential lead compound in treating myeloproliferative neoplasms and inflammatory diseases.
基于 JAK2 和 BRD4 在 NF-κB 通路中的药理学协同作用，以及 JAK2 和 BRD4 抑制剂联合治疗 MPN 和炎症的积极治疗效果。我们设计、制备并评估了一系列独特的 9H-嘌呤-2,6-二胺衍生物，它们对 Janus 激酶 2（JAK2）和 BRD4（BD2）具有选择性抑制作用。其中，化合物 9j 对 BRD4 的 BD2 和 JAK2 的 IC 值分别为 13 和 22 nM，具有可接受的抑制活性。Western blot 分析表明，化合物 9j 在 NF-κB 通路和 RAW264.7 细胞系中 p65、IκB-α 和 IKKα/β 的磷酸化信号强度方面表现出良好的功能活性。此外，9j 显著改善了 Ba/F3-JAK2 同种异体移植模型中的疾病症状。同时，9j 在急性溃疡性结肠炎模型中也有效缓解了症状。综上所述，9j 是一种有效的 JAK2/BRD4（BD2）双重靶标抑制剂，可能成为治疗骨髓增生性肿瘤和炎症性疾病的潜在先导化合物。
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