扎尔鲁卡斯特
化学
药物重新定位
药理学
药品
生物化学
生物
受体
敌手
作者
Wei‐Ping Huang,Jiaxi Wang,Xiaofei Shen,Yuqin Lei,Xueqin Chen,Da Jia,Xia Zhang,Qingxiang Sun
标识
DOI:10.1021/acs.jmedchem.2c01772
摘要
Chromosomal region maintenance protein 1 (CRM1) is a validated anticancer drug target, and its covalent inhibitor KPT-330 has been approved for marketing. However, the development of CRM1 inhibitors, especially the noncovalent ones, is still very limited. Drug repurposing is an effective strategy to develop drug leads for new targets. In this work, we virtually screened a library of marketed drugs and identified zafirlukast as a new CRM1 inhibitor. Biochemical and structural analysis revealed that zafirlukast was a noncovalent CRM1 inhibitor that bound to four subpockets in the nuclear-export-signal (NES) groove. Methylation of the sulfonamide group rendered zafirlukast completely inactive against CRM1. Zafirlukast inhibited the growth of a variety of cancer cells and worked synergistically with the drug doxorubicin. Taken together, these works laid a solid foundation for reshaping zafirlukast as a valuable lead compound for further design of noncovalent, specific, and potent CRM1 inhibitors toward the treatment of various cancers.
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