State Key Laboratory of Reliability and Intelligence of Electrical Equipment, Hebei University of Technology, Tianjin, China; Key Laboratory of Electromagnetic Field and Electrical Apparatus Reliability of Hebei Province, Hebei University of Technology, Tianjin, China; Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Science, Hebei University of Technology, Tianjin, China.
Key Laboratory of Molecular Biophysics, Hebei Province, Institute of Biophysics, School of Science, Hebei University of Technology, Tianjin, China.
J Biol Chem. 2022 Mar;298(3):101731. doi: 10.1016/j.jbc.2022.101731. Epub 2022 Feb 15.
Lung cancer has the highest mortality among cancers worldwide due to its high incidence and lack of the effective cures. We have previously demonstrated that the membrane ion channel TMEM16A is a potential drug target for the treatment of lung adenocarcinoma and have identified a pocket of inhibitor binding that provides the basis for screening promising new inhibitors. However, conventional drug discovery strategies are lengthy and costly, and the unpredictable side effects lead to a high failure rate in drug development. Therefore, finding new therapeutic directions for already marketed drugs may be a feasible strategy to obtain safe and effective therapeutic drugs. Here, we screened a library of over 1400 Food and Drug Administration-approved drugs through virtual screening and activity testing. We identified a drug candidate, Zafirlukast (ZAF), clinically approved for the treatment of asthma, that could inhibit the TMEM16A channel in a concentration-dependent manner. Molecular dynamics simulations and site-directed mutagenesis experiments showed that ZAF can bind to S387/N533/R535 in the nonselective inhibitor binding pocket, thereby blocking the channel pore. Furthermore, we demonstrate ZAF can target TMEM16A channel to inhibit the proliferation and migration of lung adenocarcinoma LA795 cells. In vivo experiments showed that ZAF can significantly inhibit lung adenocarcinoma tumor growth in mice. Taken together, we identified ZAF as a novel TMEM16A channel inhibitor with excellent anticancer activity, and as such, it represents a promising candidate for future preclinical and clinical studies.
由于肺癌发病率高且缺乏有效治疗方法，其死亡率在全球癌症中位居首位。我们之前已经证明，膜离子通道 TMEM16A 是治疗肺腺癌的潜在药物靶点，并确定了一个抑制剂结合口袋，为筛选有前途的新抑制剂提供了基础。然而，传统的药物发现策略耗时且昂贵，不可预测的副作用导致药物开发的失败率很高。因此，寻找已上市药物的新治疗方向可能是获得安全有效的治疗药物的可行策略。在这里，我们通过虚拟筛选和活性测试筛选了超过 1400 种美国食品和药物管理局批准的药物文库。我们确定了一种药物候选物，扎鲁司特（ZAF），它已被临床批准用于治疗哮喘，可浓度依赖性地抑制 TMEM16A 通道。分子动力学模拟和定点突变实验表明，ZAF 可以结合到非选择性抑制剂结合口袋中的 S387/N533/R535 上，从而阻断通道孔。此外，我们证明 ZAF 可以靶向 TMEM16A 通道抑制肺腺癌 LA795 细胞的增殖和迁移。体内实验表明，ZAF 可显著抑制小鼠肺腺癌肿瘤生长。总之，我们确定 ZAF 是一种新型的 TMEM16A 通道抑制剂，具有优异的抗癌活性，因此它是未来临床前和临床研究的有前途的候选药物。
