| Autor: |
Liu H; MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning 116023, China., Shen C; Innovation Institute for Articial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China., Li H; MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning 116023, China., Hou T; Innovation Institute for Articial Intelligence in Medicine of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China., Yang Y; MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning 116023, China.; Affiliated Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang 110042, China. |
| Abstrakt: |
CRM1 (chromosomal region maintenance 1, also referred to as exportin 1 or XPO1) plays a crucial role in maintaining the appropriate nuclear levels of tumor suppressor proteins (TSPs), growth regulatory proteins (GRPs), and antiapoptotic proteins, thereby contributing significantly to their anticancer effects. Dysregulation of CRM1-mediated nuclear transport, observed in a range of cancers such as colon cancer as well as autoimmune diseases, highlights its significance in various disease processes. In this paper, we employed a customized structure-based virtual screening campaign to search for novel covalent CRM1 inhibitors and purchased 50 potentially active compounds for in vitro bioassays. Among these candidates, AN-988 displayed a notably higher binding affinity ( K D = 615 nM) toward CRM1, as determined by the biolayer interferometry (BLI) assay. Furthermore, AN-988 exhibited a strong suppression of colorectal cancer cell proliferation and remarkable anti-inflammatory effects. Notably, AN-988 induced cell apoptosis and cell cycle arrest in a time- and dose-dependent manner by effectively inhibiting the translocation of FOXO3a from the nucleus to the cytosol, thereby preserving the activity of FOXO3a. Collectively, our study identified AN-988 as a promising CRM1 inhibitor, underscoring its potential as a preclinical colon cancer therapy candidate. |
