Rational Design of 5‑(4-(Isopropylsulfonyl)­phenyl)-3-(3-(4-((methylamino)­methyl)­phenyl)­isoxazol-5-yl)­pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor

The DNA damage response (DDR) is
a DNA damage surveillance and
repair mechanism that can limit the effectiveness of radiotherapy
and DNA-damaging chemotherapy, commonly used treatment modalities
in cancer. Two related kinases, ataxia telangiectasia mutated (ATM)
and ATM and Rad3-related kinase (ATR), work together as apical proteins
in the DDR to maintain genome stability and cell survival in the face
of potentially lethal forms of DNA damage. However, compromised ATM
signaling is a common characteristic of tumor cells, which places
greater reliance on ATR to mediate the DDR. In such circumstances,
ATR inhibition has been shown to enhance the toxicity of DNA damaging
chemotherapy to many cancer cells in multiple preclinical studies,
while healthy tissue with functional ATM can tolerate ATR inhibition.
ATR therefore represents a very attractive anticancer target. Herein
we describe the discovery of VX-970/M6620, the first ATR inhibitor
to enter clinical studies, which is based on a 2-aminopyrazine core
first reported by Charrier (J. Med. Chem. 2011, 54, 2320–2330, DOI: 10.1021/jm101488z).