Abstract 2348: Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients.

Abstract

Abstract AZD6738 is a potent and selective inhibitor of ataxia telangiectasia and rad3 related (ATR) kinase with the potential to be used in the clinic. We report the discovery of a morpholino-pyrimidine series and its subsequent optimisation to the pre-clinical candidate AZD6738 which has a good overall balance of potency, selectivity, pharmacokinetic and biopharmaceutical properties suitable for oral dosing. ATR is a serine/threonine protein kinase involved in DNA damage response signalling caused by DNA replication associated stress. Activation of ATR at stalled replication forks leads to suppression of replication fork origin firing, promotes repair and S/G2-cell cycle checkpoints to prevent premature mitosis and maintain genomic integrity. Failure to resolve damage leads to genomic instability and if sufficiently high, cell death. Stalled replication forks may collapse leading to formation of DNA double stranded breaks and activation of the ataxia telangiectasia mutated (ATM) kinase. ATM works in conjunction with ATR to efficiently resolve replication associated DNA damage creating a co-dependency with loss of one leading to a greater reliance on the other to maintain genomic stability. ATM is frequently inactivated across B-cell malignancies, head and neck, breast and lung cancers through chromosomal deletion, promoter hypermethylation or mutation. ATM-deficient tumours are hypothesised to be more reliant on ATR for survival and specific inhibition of ATR may lead enhanced anti-tumour activity while minimizing normal tissue toxicity. AZD6378 has the potential to test the clinical efficacy of ATR inhibition in cancer patients as monotherapy against ATM-deficient tumours or in combination with chemo or radiotherapy. Citation Format: Clifford D. Jones, Kevin Blades, Kevin M. Foote, Sylvie M. Guichard, Philip J. Jewsbury, Thomas McGuire, Johannes W. Nissink, Rajesh Odedra, Kin Tam, Pia Thommes, Paul Turner, Gary Wilkinson, Christine Wood, James W. Yates. Discovery of AZD6738, a potent and selective inhibitor with the potential to test the clinical efficacy of ATR kinase inhibition in cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2348. doi:10.1158/1538-7445.AM2013-2348