Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; School of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA 30332-0250, USA.
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Bioorg Med Chem Lett. 2021 Feb 1;33:127745. doi: 10.1016/j.bmcl.2020.127745. Epub 2020 Dec 15.
BAZ1A is a bromodomain-containing protein, and has been recognized as a potential target for multiple diseases, particularly cancer. However, there is no BAZ1A inhibitor reported so far. In this study, we used a consensus docking/scoring strategy to screen for BAZ1A bromodomain inhibitors from commercial chemical libraries and an in-house chemical database. The retrieved hit compounds were evaluated experimentally and four compounds were found to be active against BAZ1A bromodomain. To the most active compounds, similarity and substructure searches were used to find more BAZ1A bromodomain inhibitors. Among all the obtained active compounds, Cpd-2 is the most potent one, which showed a K value of 0.52 μM. The interaction model of Cpd-2 with BAZ1A bromodomain was revealed by molecular docking. In a cellular assay, Cpd-2 displayed good anti-viability activity against cancer cell lines expressing a high level of BAZ1A. Overall, we discovered a number of BAZ1A bromodomain inhibitors for the first time, which can be a good starting point for subsequent drug discovery targeting BAZ1A bromodomain.
BAZ1A 是一种含有溴结构域的蛋白，已被认为是多种疾病（特别是癌症）的潜在靶点。然而，到目前为止还没有报道的 BAZ1A 抑制剂。在这项研究中，我们使用共识对接/评分策略从商业化学文库和内部化学数据库中筛选 BAZ1A 溴结构域抑制剂。检索到的命中化合物通过实验进行了评估，发现有 4 种化合物对 BAZ1A 溴结构域具有活性。对于最有效的化合物，进行了相似性和子结构搜索，以找到更多的 BAZ1A 溴结构域抑制剂。在所获得的所有活性化合物中，CpD-2 的活性最强，其 K 值为 0.52 μM。通过分子对接揭示了 CpD-2 与 BAZ1A 溴结构域的相互作用模型。在细胞测定中，CpD-2 对表达高水平 BAZ1A 的癌细胞系表现出良好的抗活力活性。总的来说，我们首次发现了多种 BAZ1A 溴结构域抑制剂，这可为随后针对 BAZ1A 溴结构域的药物发现提供一个良好的起点。
