7YPZ

Zafirlukast in complex with CRM1-Ran-RanBP1

Summary for 7YPZ

• Entry DOI: 10.2210/pdb7ypz/pdb
• Descriptor: GTP-binding nuclear protein Ran, GLYCEROL, 3[N-MORPHOLINO]PROPANE SULFONIC ACID, ... (13 entities in total)
• Functional Keywords: active ran, complex, transport protein, inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 158591.94

Authors

Sun, Q.,Lei, Y. (deposition date: 2022-08-05, release date: 2023-08-16, Last modification date: 2024-05-08)

Primary citation

Huang, W.,Wang, J.X.,Shen, X.,Lei, Y.,Chen, X.,Jia, D.,Zhang, X.,Sun, Q.
Searching for Novel Noncovalent Nuclear Export Inhibitors through a Drug Repurposing Approach.
J.Med.Chem., 66:1574-1582, 2023

PubMed 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.

PubMed: 36622814
DOI: 10.1021/acs.jmedchem.2c01772

Experimental method

X-RAY DIFFRACTION (2.15 Å)