药物重新定位
坎德萨坦
药理学
药品
化学
IC50型
体内
医学
生物化学
生物
体外
受体
血管紧张素II
生物技术
作者
Qiushuang Ji,Sai Shi,Biao Ma,Weiwei Zhang,Hailong An,Shuai Guo
标识
DOI:10.1016/j.ijbiomac.2023.123839
摘要
TMEM16A, a Ca2+-activated chloride channel (CaCC), and its pharmacological inhibitors can inhibit the growth of lung adenocarcinoma cells. However,the poor efficacy, safety, and stability of TMEM16A inhibitors limit the development of these agents. Therefore, finding new therapeutic directions from already marketed drugs is a feasible strategy to obtain safe and effective therapeutic drugs. Here, we screened a library contain more than 2400 FDA, EMA, and NMPA-approved drugs through virtual screening. We identified a drug candidate, candesartan (CDST), which showed strong inhibitory effect on the TMEM16A in a concentration-dependent manner with an IC50 of 24.40 ± 3.21 μM. In addition, CDST inhibited proliferation, migration and induced apoptosis of LA795 cells targeting TMEM16A, and significantly inhibited lung adenocarcinoma tumor growth in vivo. The molecular mechanism of CDST inhibiting TMEM16A channel indicated it bound to R515/R535/E623/E624 in the drug pocket, thereby blocked the pore. In conclusion, we identified a novel TMEM16A channel inhibitor, CDST, which exhibited excellent inhibitory activity against lung adenocarcinoma. Considering that CDST has been used in clinical treatment of hypertension, it may play an important role in the combined treatment of hypertension and lung adenocarcinoma as a multi-target drug in the future.
科研通智能强力驱动
Strongly Powered by AbleSci AI