Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan 610041, China.
Bioorg Med Chem Lett. 2021 Aug 1;45:128139. doi: 10.1016/j.bmcl.2021.128139. Epub 2021 May 25.
Jumonji-C (JmjC) domain-containing 7 (JMJD7), which is a 2-oxoglutarate (2OG)-dependent oxygenase, has been demonstrated to play an important role in the occurrence and development of a number of diseases, particularly cancer. Discovery of JMJD7 inhibitors is thus of great importance. Herein consensus docking/scoring strategy and bioactivity evaluation were used to identify JMJD7 inhibitors from various chemical databases. Seven active compounds were retrieved. The most potent compound, Cpd-3, showed an IC value of 6.62 μM against JMJD7. Further biophysical assays confirmed that Cpd-3 could efficiently bind to JMJD7 in vitro. Flexible docking was used to predict the binding mode of Cpd-3 with JMJD7. In a cellular assay, Cpd-3 displayed good inhibitory activity against cancer cell lines expressing a high level of JMJD7. As far as we know, Cpd-3 is the first JMJD7 inhibitor reported so far. Overall, this study established a good starting point for drug discovery targeting JMJD7.
组蛋白赖氨酸特异性去甲基化酶 7（JMJD7）是一种依赖 2-氧戊二酸（2OG）的氧合酶，已被证明在许多疾病的发生和发展中发挥着重要作用，尤其是癌症。因此，发现 JMJD7 抑制剂具有重要意义。在此，我们采用共识对接/评分策略和生物活性评价方法，从各种化学数据库中筛选出 JMJD7 抑制剂。共检索到 7 种活性化合物。其中，活性最强的化合物 Cpd-3 对 JMJD7 的 IC 值为 6.62 μM。进一步的生物物理测定证实，Cpd-3 可以在体外有效地与 JMJD7 结合。柔性对接用于预测 Cpd-3 与 JMJD7 的结合模式。在细胞实验中，Cpd-3 对表达高水平 JMJD7 的癌细胞系表现出良好的抑制活性。据我们所知，Cpd-3 是迄今为止报道的首个 JMJD7 抑制剂。总的来说，这项研究为针对 JMJD7 的药物发现奠定了良好的基础。
