Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Microsatellite-instable (MSI) cancers exhibit replication stress due to expanded DNA (TA)n repeats, creating a dependency on WRN helicase.
• WRN helicase is a validated synthetic lethal target for MSI tumors, with inhibitors currently under development.

Purpose of the Study:

• To map critical WRN residues in MSI cells using CRISPR-Cas9 base editing.
• To develop potent and selective WRN helicase covalent inhibitors for MSI cancer therapy.
• To evaluate the efficacy and biomarker associations of these inhibitors in preclinical models.

Main Methods:

• CRISPR-Cas9 base editing to identify key WRN residues.
• Fragment-based screening for inhibitor development.
• In vitro and in vivo studies using MSI cancer models, organoids, and patient-derived xenografts.
• Biomarker analysis including TA-repeat expansions and mismatch repair alterations.

Main Results:

• Validated the WRN helicase domain as the primary drug target.
• Developed potent and selective covalent WRN helicase inhibitors.
• Demonstrated selective suppression of MSI model growth, induction of DNA double-strand breaks at expanded TA repeats, and DNA damage.
• Confirmed efficacy in immunotherapy-resistant models and identified predictive biomarkers.

Conclusions:

• The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer.
• These inhibitors offer a potential new therapeutic strategy for MSI cancers, including those resistant to immunotherapy.
• The developed compounds serve as valuable tools for further investigation of WRN biology and cancer therapy.