Abstract 369: Antitumor activity of M4344, a potent and selective ATR inhibitor, in monotherapy and combination therapy

The protein kinase ataxia telangiectasia mutated and Rad3-related ATR is one of the key mediators of the DNA damage response. ATR is recruited to regions of single-stranded DNA, which most commonly arise during replication stress (RS). RS occurs during S-phase when the cell’s DNA replication machinery encounters problems such as unresolved DNA lesions. In addition, treatment of cells with DNA-damaging agents can lead to RS as cells progress to S-phase without resolving damage incurred by such agents. Elevated levels of RS are evident in some cancer cells, even in the absence of a DNA-damaging agent resulting from expression of oncogenes that drive dysregulated replication, a hypoxic environment, or from defects in other repair pathways. RS in cancer cells can drive reliance on ATR for survival and, accordingly, ATR inhibitors may have benefit as monotherapy. M4344 was determined to be an adenosine triphosphate (ATP)-competitive, highly potent, and tight-binding inhibitor of ATR with a Ki of Citation Format: Frank T. Zenke, Astrid Zimmermann, Heike Dahmen, Brian Elenbaas, John Pollard, Philip Reaper, S Bagrodia, M E. Spilker, C Amendt, Andree Blaukat. Antitumor activity of M4344, a potent and selective ATR inhibitor, in monotherapy and combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 369.