Wang Tianqi, Zhang Rong, Liu Yang, Fang Zhen, Zhang Hailin, Fan Yan, Yang Shengyong, Xiang Rong
Department of Medicinal Chemistry, School of Medicine, Nankai University, Tianjin 300071, PR China.
West China Hospital, Sichuan University, Chengdu 610041, PR China.
Bioorg Med Chem Lett. 2021 Jul 15;44:128109. doi: 10.1016/j.bmcl.2021.128109. Epub 2021 May 13.
JmjC domain-containing protein 6 (JMJD6) has been thought as a potential target for various diseases particularly cancer. However, few selective JMJD6 inhibitors have been reported. In this investigation, molecular docking and biological activity evaluation were performed to retrieve new JMJD6 inhibitors, which led to the identification of a hit compound, J2. Further structural optimization and structure-activity relationship (SAR) analysis towards J2 were carried out, which gave a new potent JMJD6 inhibitor, 7p. This compound showed an IC value of 0.681 μM against JMJD6, but displayed no activity against other tested JmjC domain-containing protein family members, indicating good selectivity (>100 fold). Collectively, this investigation offers a selective JMJD6 inhibitor, which could be taken as a lead compound for subsequent drug discovery targeting JMJD6.
含JmjC结构域蛋白6（JMJD6）被认为是各种疾病尤其是癌症的潜在靶点。然而，报道的选择性JMJD6抑制剂很少。在本研究中，进行了分子对接和生物活性评估以寻找新的JMJD6抑制剂，从而鉴定出一个活性化合物J2。对J2进行了进一步的结构优化和构效关系（SAR）分析，得到了一种新的强效JMJD6抑制剂7p。该化合物对JMJD6的IC值为0.681μM，但对其他测试的含JmjC结构域蛋白家族成员无活性，表明具有良好的选择性（>100倍）。总的来说，本研究提供了一种选择性JMJD6抑制剂，可作为后续针对JMJD6进行药物研发的先导化合物。
