Jiang Hao, Xing Jing, Wang Chen, Zhang Hao, Yue Liyan, Wan Xiaozhe, Chen Wei, Ding Hong, Xie Yiqian, Tao Hongru, Chen Zhifeng, Jiang Hualiang, Chen Kaixian, Chen Shijie, Zheng Mingyue, Zhang Yuanyuan, Luo Cheng
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
Org Biomol Chem. 2017 Nov 15;15(44):9352-9361. doi: 10.1039/c7ob02369c.
The BET family of bromodomain-containing proteins (BRDs) is believed to be a promising drug target for therapeutic intervention in a number of diseases including cancer, inflammation and cardiovascular diseases. Hence, there is a great demand for novel chemotypes of BET inhibitors. The drug repurposing strategy offers great benefits to find inhibitors with known safety and pharmacokinetic profiles, thus increasing medicinal chemists' interest in recent years. Using the drug repurposing strategy, a BRD4-specific score based virtual screening campaign on an in-house drug library was conducted followed by the ALPHA screen assay test. Nitroxoline, an FDA-approved antibiotic, was identified to effectively disrupt the interaction between the first bromodomain of BRD4 (bromodomain-containing protein 4) and acetylated H4 peptide with IC of 0.98 μM. Nitroxoline inhibited all BET family members with good selectivity against non-BET bromodomain-containing proteins, thus it is defined as a selective BET inhibitor. Based on the crystal structure of the nitroxoline-BRD4_BD1 complex, the mechanism of action as well as BET specificity of nitroxoline were determined. Since the anticancer activity of nitroxoline against MLL leukemia, one of the BET related diseases, has not been studied before, we tested whether nitroxoline might serve as a potential repurposing drug candidate for MLL leukemia. Nitroxoline effectively inhibited the proliferation of MLL leukemia cells by inducing cell cycle arrest and apoptosis. The profound efficacy is, at least in part, due to the inhibition of BET and downregulation of target gene transcription. Our discovery of nitroxoline as a BET inhibitor suggests potential application of nitroxoline and its derivatives for clinical translation in BET family related diseases.
含溴结构域蛋白（BRD）的BET家族被认为是治疗包括癌症、炎症和心血管疾病在内的多种疾病的一个有前景的药物靶点。因此，对新型BET抑制剂化学类型有很大需求。药物重新利用策略为寻找具有已知安全性和药代动力学特征的抑制剂提供了巨大优势，从而在近年来增加了药物化学家的兴趣。利用药物重新利用策略，对内部药物库进行了基于BRD4特异性评分的虚拟筛选，随后进行了Alpha筛选试验。硝氧喹啉是一种经美国食品药品监督管理局批准的抗生素，被确定能有效破坏BRD4（含溴结构域蛋白4）的第一个溴结构域与乙酰化H4肽之间的相互作用，其半数抑制浓度为0.98 μM。硝氧喹啉抑制所有BET家族成员，对不含BET溴结构域的蛋白具有良好的选择性，因此它被定义为一种选择性BET抑制剂。基于硝氧喹啉 - BRD4_BD1复合物的晶体结构，确定了硝氧喹啉的作用机制以及BET特异性。由于此前尚未研究过硝氧喹啉对BET相关疾病之一的MLL白血病的抗癌活性，我们测试了硝氧喹啉是否可能作为MLL白血病的一种潜在的重新利用药物候选物。硝氧喹啉通过诱导细胞周期停滞和凋亡有效抑制MLL白血病细胞的增殖。这种显著的疗效至少部分归因于对BET的抑制和靶基因转录的下调。我们发现硝氧喹啉作为一种BET抑制剂，表明硝氧喹啉及其衍生物在BET家族相关疾病临床转化中的潜在应用。
