A new investigational cancer drug, ATRN-119, is showing promise as a treatment for tumors with mutations in DNA repair genes, particularly those with ATM loss-of-function. The molecule, currently in early-stage clinical trials, belongs to a class known as ATR inhibitors, drugs designed to disrupt cancer cells’ ability to survive DNA damage. What sets this candidate apart is its macrocyclic structure, which offers high selectivity for ATR (Ataxia Telangiectasia and Rad3-related protein), a key regulator in the DNA damage response.

Cancer cells with ATM mutations are particularly dependent on ATR to manage the stress caused by uncontrolled growth and faulty DNA repair. Blocking ATR in these cells can trigger lethal DNA damage, a concept known as synthetic lethality. The drug’s design aims to exploit this vulnerability while sparing healthy cells, which do not share the same dependency on ATR.

Three patients receiving 550 mg of the investigational drug twice daily experienced tumor shrinkage of 7%, 14%, and 21%, respectively — all before reaching the expected Phase 2 dose. Notably, these results were achieved with the drug used as a monotherapy (ART0380 is another ATR inhibitor that showed impressive results, though in combination with irinotecan).

Importantly, ATRN-119 has shown minimal hematological toxicity, a significant improvement over other drugs in this class, which often cause bone marrow suppression. This clean safety profile could allow for continuous dosing and makes the drug a strong candidate for combination therapies with other agents such as PARP inhibitors.

With ATM mutations present in a substantial fraction of solid tumors—up to 24%—this approach could offer a much-needed option for a wide range of patients.

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