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Discovery of Potent Covalent CRM1 Inhibitors Via a Customized Structure-Based Virtual Screening Pipeline and
He Liu1, Chao Shen2, Haonan Li1
1MOE Key Laboratory of Bio-Intelligent Manufacturing, School of Bioengineering, Dalian University of Technology, Dalian, Liaoning 116023, China.
Abstract:
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 (KD = 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.
Insights
A novel covalent inhibitor, AN-988, targets CRM1 (chromosomal region maintenance 1) to suppress colorectal cancer cell proliferation and inflammation. This compound shows promise as a potential preclinical colon cancer therapy.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- CRM1 (chromosomal region maintenance 1) is vital for nuclear transport of tumor suppressors and growth regulators, with dysregulation linked to cancer and autoimmune diseases.
- Targeting CRM1 offers a therapeutic strategy for various diseases, including colon cancer.
Purpose of the Study:
- To identify novel covalent CRM1 inhibitors using structure-based virtual screening.
- To evaluate the efficacy of identified inhibitors, particularly AN-988, in preclinical models of colon cancer.
Main Methods:
- Structure-based virtual screening to identify potential CRM1 inhibitors.
- In vitro bioassays, including biolayer interferometry (BLI), to assess binding affinity.
- Cell proliferation, apoptosis, and cell cycle assays to evaluate AN-988's effects on colorectal cancer cells.
Main Results:
- AN-988 demonstrated high binding affinity (KD = 615 nM) to CRM1.
- AN-988 significantly suppressed colorectal cancer cell proliferation and exhibited anti-inflammatory effects.
- AN-988 induced time- and dose-dependent apoptosis and cell cycle arrest by inhibiting FOXO3a nuclear export.
Conclusions:
- AN-988 is a potent covalent CRM1 inhibitor with demonstrated preclinical efficacy against colon cancer.
- AN-988's mechanism involves preserving FOXO3a activity, suggesting its potential as a novel colon cancer therapeutic agent.
