Mechanism of CRM1 Inhibition by Lansoprazole and Its Synergy with Cisplatin in Gastric Cancer

  • J Med Chem. 2026 May 28;69(10):11705-11719. doi: 10.1021/acs.jmedchem.6c01114.
Yubin Luo  1  2 ,  Qiaohua Yan  1 ,  Bingzhou Huang  1 ,  Youfu Luo  2 ,  Ting Yu  3 ,  Qiao Zhou  3 ,  Chenhui Wang  4 ,  Minghai Tang  5 ,  Qingxiang Sun  1
Affiliations
  • 1. Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu 610032, China.
  • 2. Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 3. Pathology Department, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
  • 4. The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610032, China.
  • 5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China.
PMID: 42134807 DOI: 10.1021/acs.jmedchem.6c01114
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.

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