Novel compounds targeting ATR-kinase for treating cancer

DNA lesions occur in all living organisms. As accumulating DNA damage poses a risk for cell survival, cells harbour sophisticated mechanisms for repairing such lesions. The kinase ATR (“ATM and Rad3 related”) is a key player in triggering the cellular response to double strand DNA breaks called “DNA Damage Response” (“DDR”) thereby enabling DNA repair and thus promoting cell survical.

As cancer cells are often characterized by defects in various DNA repair processes and/or DNA damages, intact ATR-signalling (and subsequent DNA-repair processes) is particularly crucial for the viability of such cancer cells.

In fact, blocking DDR, preferably by inhibiting ATR has become an attractive therapeutic concept.

Correspondingly, at present, two ATR inhibitors (VX-970 and AZD5738; for ref. see “Relevant Publications”) have already entered clinical studies.

However, both with the developmental risk associated with these compounds, the need for compounds displaying an improved safety-/efficacy-profile and the large number of patients, there is a huge interest in advanced ATR inhibitors.

The present invention thus relates to advanced ATR antagonists which have proven to be effective in various in cellular assays (both on its own and in combination with cisplatin). Furthermore they show a promising ADME-profile as deducted from predictive ADME modelling and an improved solulibility in relation to the aforementioned compounds.

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