Discovery and Characterization of Small Molecule Inhibitors Targeting Exonuclease 1 for Homologous
Yixing Wang1, Jessica D Hess1, Chen Wang1
1Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, California 91010, United States.
ACS Chemical Biology
|May 16, 2025
Summary
New compounds targeting Human Exonuclease 1 (EXO1) show promise for treating homologous recombination deficient (HRD) cancers. These EXO1 inhibitors exploit synthetic lethality in BRCA1-deficient cells, offering a targeted therapeutic strategy.
Area of Science:
- Molecular Biology
- Cancer Therapeutics
- Genetics
Background:
- Human Exonuclease 1 (EXO1) is crucial for genome stability, processing DNA breaks and replication intermediates.
- Its role in homologous recombination (HR) and replication fork processing makes EXO1 a significant therapeutic target in cancer.
Purpose of the Study:
- To identify and characterize novel small molecule inhibitors of EXO1.
- To evaluate the therapeutic potential of EXO1 inhibitors in HR-deficient (HRD) cancers.
Main Methods:
- High-throughput screening of 45,000 compounds to identify EXO1 inhibitors.
- Docking analysis, site-directed mutagenesis, and biochemical assays to determine binding mechanisms and inhibitory activity.
- Tumor cell profiling in BRCA1-deficient cells to assess synthetic lethality.
Main Results:
- Seven distinct chemical scaffolds inhibiting EXO1 were identified, with C200 and F684 showing high potency.
- Inhibitors demonstrated potent and selective inhibition of EXO1 nuclease activity.
- EXO1 inhibition induced synthetic lethality in BRCA1-deficient cells, suppressed DNA end resection, and increased DNA double-strand breaks.
Conclusions:
- EXO1 inhibitors are effective in targeting HRD cancers, particularly those with BRCA1/2 mutations.
- These compounds disrupt essential DNA repair pathways, leading to cancer cell death.
- EXO1 inhibitors represent promising candidates for targeted cancer therapy development.
