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The ATR (ATM and Rad3 related) kinase plays a crucial role in maintaining genome integrity during DNA replication and is involved in the coordination of the DNA damage response (“DDR”) and repair signaling pathways. Activation of ATR is directly triggered by DNA lesions facilitating DNA repair and thus promotes tumor cell survival.
Therapeutic inhibition of ATR can reverse this mechanism and thereby increase tumor cell killing. Preventing ATR signaling from stalled replication forks enhances the formation of DNA damage, especially under conditions of increased replication stress as typically observed in cancer cells. Therefore, ATR inhibitors can potentiate the effect of chemotherapy or radiation, which makes ATR an attractive target for cancer therapy.
At present, two ATR inhibitors (VX-970 and AZD6738; for ref. see “Relevant publication”) have already entered clinical studies.
However, with the developmental risks associated with these compounds, there is a huge interest in advanced ATR inhibitors displaying an improved safety-/efficacy-profile.
The present invention thus relates to advanced ATR antagonists, which have been shown to be effective in various cellular assays (both on its own in Burkitt Lymphoma and in combination with cisplatin). Furthermore, they show a promising ADME-profile as deducted from predictive ADME modeling in relation to the aforementioned ATR inhibitors.
Keywords: ATR, Krebs, Onkologie, Antagonist, DNS-Reparatur, Kinase, Inhibitor, Signaltransduktion, DNS-Schäden, Therapie, Wirkstoff, ATR, cancer, oncology, antagonist, DNA-repair, kinase, inhibitor, signal transduction, DNA damage, therapy, compound, NCE, DNA damage response, DDR, Pharma, Therapie, Patienten, RWTH
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Furthermore they show a promising ADME-profile as deducted from predictive ADME modelling and an improved solulibility in relation to the aforementioned compounds.
On behalf of RWTH Aachen University, PROvendis offers licenses for commercial use as well a research collaboration with licensing option.
A priority patent application has been filed.
Llona-Minguez et al. (2014) Chemical strategies for development of ATR inhibitors. Exp. Rev. Mol. Med. 16: e10
Fokas, E. et al. (2014) Targeting ATR in DNA damage response and cancer therapeutics. Cancer Treat Rev. 40(1): 109-17
International Patent Application WO 2011/154737
International Patent Application WO 2010/071837
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