ATR is a key regulator of the cell response to replication stress, a potentially lethal form of DNA damage that arises when cells attempt to replicate damaged DNA. Drugs that induce such DNA damage have been the cornerstone for cancer therapy for decades. However, the clinical benefit of these agents is limited by poor differentiation between toxicity in cancer and normal cells, and because most cells are capable of repairing the damaged DNA. It has been shown that many cancer cells are more reliant on ATR for survival from DNA damage than normal cells and consequently, inhibitors of ATR could improve the efficacy of DNA damaging agents.Herein we describe the discovery of selective ATR inhibitors. The relationships between the structure of these aminopyrazines, their potency and selectivity will be presented along with characteristics of the most advanced compound, VX-970 (VE-822). This compound inhibits the ATR kinase with Ki<0.3nM via an ATP competitive mechanism of action. It markedly enhances the cytotoxic activity of DNA damaging drugs in many cancer cells but is well tolerated by normal cells. In a panel of patient-derived mouse xenograft cancer models, administration of VX-970 dramatically improved cisplatin efficacy without increasing toxicity.The pre-clinical profile for this series of compounds show that ATR inhibitors have great potential to improve the clinical benefit of a range of established DNA damaging drugs.

Discovery of ATR selective inhibitors for the treatment of cancer

248th National Meeting (2014)

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