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Updated: Jul 8, 2025
Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO
Published on: December 28, 2019
Discovery of a Hidden Pocket beneath the NES Groove by Novel Noncovalent CRM1 Inhibitors
Cong Li1,2, Qian Zhang1,3, Wenxin Huang1,2
1Department of Pathology, State Key Laboratory of Biotherapy, and Collaborative Innovation Centre of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Abstract:
Protein localization is frequently manipulated to favor tumor initiation and progression. In cancer cells, the nuclear export factor CRM1 is often overexpressed and aberrantly localizes many tumor suppressors via protein-protein interactions. Although targeting protein-protein interactions is usually challenging, covalent inhibitors, including the FDA-approved drug KPT-330 (selinexor), were successfully developed. The development of noncovalent CRM1 inhibitors remains scarce. Here, by shifting the side chain of two methionine residues and virtually screening against a large compound library, we successfully identified a series of noncovalent CRM1 inhibitors with a stable scaffold. Crystal structures of inhibitor-protein complexes revealed that one of the compounds, B28, utilized a deeply hidden protein interior cavity for binding. SAR analysis guided the development of several B28 derivatives with enhanced inhibition on nuclear export and growth of multiple cancer cell lines. This work may benefit the development of new CRM1-targeted therapies.
Insights
Researchers identified novel noncovalent inhibitors targeting the CRM1 protein, crucial in cancer progression. These compounds show potential for developing new cancer therapies by blocking aberrant protein export.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The nuclear export factor CRM1 is overexpressed in cancer, mislocalizing tumor suppressors via protein-protein interactions.
- Targeting protein-protein interactions is challenging; covalent inhibitors exist, but noncovalent CRM1 inhibitors are scarce.
- Aberrant CRM1 activity promotes tumor initiation and progression.
Purpose of the Study:
- To identify novel noncovalent inhibitors of CRM1.
- To develop new therapeutic strategies targeting CRM1 in cancer.
Main Methods:
- Utilized computational screening and medicinal chemistry approaches.
- Modified methionine residues and screened compound libraries.
- Determined crystal structures of inhibitor-protein complexes.
- Conducted structure-activity relationship (SAR) analysis.
Main Results:
- Identified a series of stable, noncovalent CRM1 inhibitors.
- Discovered a lead compound, B28, binding to a hidden protein cavity.
- Developed B28 derivatives with enhanced CRM1 inhibition.
- Demonstrated inhibition of cancer cell line growth.
Conclusions:
- Novel noncovalent CRM1 inhibitors were successfully developed.
- The lead compound B28 and its derivatives show therapeutic potential.
- This research may advance the development of CRM1-targeted cancer therapies.
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