9X7O

Lansoprazole derivative in complex with CRM1-Ran-RanBP1

This is a non-PDB format compatible entry.

Summary for 9X7O

• Entry DOI: 10.2210/pdb9x7o/pdb
• Descriptor: GTP-binding nuclear protein Ran, [1-(1H-benzimidazol-2-yl)-3-methyl-4-[2,2,2-tris(fluoranyl)ethoxy]pyridin-1-ium-2-yl]methanethiol, Ran-specific GTPase-activating protein 1, ... (11 entities in total)
• Functional Keywords: nuclear export inhibitor, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 157791.88

Authors

Sun, Q.,Luo, Y. (deposition date: 2025-10-17, release date: 2026-06-03, Last modification date: 2026-06-10)

Primary citation

Luo, Y.,Yan, Q.,Huang, B.,Luo, Y.,Yu, T.,Zhou, Q.,Wang, C.,Tang, M.,Sun, Q.
Mechanism of CRM1 Inhibition by Lansoprazole and Its Synergy with Cisplatin in Gastric Cancer.
J.Med.Chem., 69:11705-11719, 2026

PubMed Abstract: CRM1 (Chromosome Region Maintenance 1, also known as Exportin-1 or XPO1) is a key nuclear export factor that exports and inactivates tumor suppressor proteins in cancer. Here, we report that the proton pump inhibitor lansoprazole, upon acid activation, is converted into a CRM1 inhibitor in vitro. The active component is a positively charged molecule that binds noncovalently to the nuclear export signal (NES) groove of CRM1, as revealed by biochemical studies and a 2.0 Å cocrystal structure. Interestingly, lansoprazole undergoes spontaneous activation in cells, thereby inhibiting nuclear export to a similar extent as its preacid-activated form. Since the compound is susceptible to inhibition by glutathione (GSH), we designed a combination strategy where cisplatin, by depleting GSH, synergistically enhanced CRM1 inhibition. This combination demonstrated antitumor synergy in a gastric cancer xenograft model without increasing toxicity. Our work presents a novel CRM1 inhibitor and a chemosensitization strategy for gastric cancer.

PubMed: 42134807
DOI: 10.1021/acs.jmedchem.6c01114

Experimental method

X-RAY DIFFRACTION (2 Å)