Cell-active small molecule inhibitors validate the SNM1A DNA repair nuclease as a cancer target

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Therapeutics

Background:

• The human SNM1A-C metallo-β-lactamase (MBL) fold nucleases are vital for DNA damage repair and telomere maintenance.
• Genetic studies highlight SNM1A as a potential therapeutic target for enhancing cancer treatments.

Purpose of the Study:

• To identify and optimize inhibitors of SNM1A for cancer therapy.
• To validate MBL fold nucleases as tractable targets for drug development.

Main Methods:

• High-throughput screening identified initial SNM1A inhibitor pharmacophores.
• Crystallography elucidated inhibitor binding to the SNM1A active site.
• Structure-activity relationship optimization led to quinazoline-hydroxamic acid inhibitors.

Main Results:

• Optimized inhibitors bind by displacing water and occupying the nucleobase site.
• Cellular assays demonstrated SNM1A inhibitors enhance sensitivity to cisplatin.
• Inhibitors caused defects in resolving cisplatin-induced DNA damage.

Conclusions:

• SNM1A inhibitors effectively sensitize cancer cells to DNA damaging agents.
• Metallo-β-lactamase fold nucleases are validated as promising cancer drug targets.