Identification of the first small-molecule inhibitor of the REV7 DNA repair protein interaction

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• DNA interstrand crosslink repair (ICLR) is crucial for cancer cell resistance to chemotherapy.
• Targeting ICLR with small-molecule inhibitors offers a promising strategy to overcome treatment resistance.
• Mammalian DNA polymerase ζ (REV3L/REV7) is essential for ICLR.

Purpose of the Study:

• To identify small-molecule inhibitors targeting REV7 for blocking ICLR.
• To investigate the potential of REV7/REV3L interaction inhibitors in chemosensitizing cancer cells.

Main Methods:

• High-throughput screening and structure-activity relationship (SAR) analysis to identify inhibitors.
• Nuclear magnetic resonance (NMR) to confirm direct binding of compounds to REV7.
• Reporter plasmid assays to assess ICLR inhibition.
• Clonogenic survival assays in HeLa cells treated with cisplatin and compound 7.

Main Results:

• Compound 1 identified as an inhibitor of REV7/REV3L interaction.
• Compound 7 directly bound to REV7 and inhibited ICLR.
• Compound 7 reduced cancer cell survival when combined with cisplatin, indicating chemosensitization.

Conclusions:

• Small-molecule inhibition of the REV7/REV3L interaction effectively blocks ICLR.
• Targeting REV7 represents a viable strategy to chemosensitize cancer cells to ICL-inducing agents.
• This study provides a foundation for developing novel cancer therapeutics that enhance chemotherapy efficacy.