2. Academic Validation
  3. Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach

  • J Med Chem. 2023 Jan 26;66(2):1574-1582. doi: 10.1021/acs.jmedchem.2c01772.
Wenxin Huang 1,  Jia-Xi Wang 1,  Xiaofei Shen 2,  Yuqin Lei 1,  Xueqin Chen 1,  Da Jia 3,  Xia Zhang 1,  Qingxiang Sun 1
Affiliations

Affiliations

  • 1 Department of Pathology, State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Collaborative Innovation Centre of Biotherapy, Sichuan University, Chengdu 610041, China.
  • 2 TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, China.
  • 3 Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Pediatrics, Division of Neurology, West China Second University Hospital, Sichuan University, Chengdu 610041, China.
PMID: 36622814 DOI: 10.1021/acs.jmedchem.2c01772
Abstract

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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