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

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.