Preclinical identification of AZD7762, a novel, potent and selective inhibitor of Checkpoint kinases

A232 Conventional DNA targeting therapies such as chemotherapy and radiation are among the most common cancer treatments. As a class, they have produced significant increases in survival of patients, particularly when used in combination with drugs with different mechanisms of action. Although DNA damage is an effective approach to tumor control, this mechanism also leads to significant side effects. Another limitation of DNA damaging agents is that many patients develop resistance and therefore become refractory to treatment. Insights from cell cycle research has led to the hypothesis that tumors may be selectivity sensitized to DNA damaging agents resulting in improved anti-tumour activity and a wider therapeutic margin. The approach relies on the observation that the majority of tumors are deficient in the G1 DNA damage checkpoint pathway resulting in reliance on S and G2 phase checkpoints to repair DNA damage and survive. The S and G2 phase checkpoints have been shown to be regulated by checkpoint kinase 1 (Chk1), a serine/threonine kinase that is activated in response to DNA damage. Inhibition of Chk1 signaling has been shown to impair DNA repair and result in increased tumor cell death. Normal tissues, however, have a functioning G1 checkpoint signaling pathway allowing for DNA repair and cell survival. Thus, the aim of our program is to develop a Chk1 kinase inhibitor that will selectively potentiate the therapeutic effects of DNA damaging agents in tumor cells. Such an agent offers the potential to enhance the efficacy of both conventional chemo- and radiotherapies and increase patient response rates in a variety of settings.
 Here we report on the screening cascade and key preclinical findings that led to the discovery of AZD7762. AZD7762 is a potent Chk1 kinase inhibitor in both an in vitro kinase assay and a cell based checkpoint abrogation assay. AZD7762 has been profiled extensively in combination with DNA damaging agents and has been shown to potentiate response in a number of different cancer cell lines. AZD7762 is also active in pharmacodynamic in vivo assay where inhibition of Chk1 results in the abrogation of DNA damage induced cell cycle arrest. Dose-dependent potentiation of anti-tumor activity in combination with DNA damaging agents has been observed in multiple xenograft models with many DNA damaging agents. Importantly, the efficacy is enhanced in both sensitive as well as relatively insensitive human tumor models in combination with AZD7762. Furthermore, increased efficacy is achieved without impacting the tolerability or MTD of the DNA damaging agent. AZD7762 is now in early clinical development.