Structure activity and structure property relationships of a novel series of potent inhibitors of Checkpoint kinases

A233 Checkpoint kinase 1 (Chk1) is a serine/threonine kinase whose expression is limited to the S and G2 phases of proliferating cells, and is absent in differentiated cells. It is phosphorylated and activated in response to DNA damage, and the result of the downstream cascade initiated by this event is to cause cell cycle arrest in the S and G2/M phases. Inhibition of Chk1 kinase activity has been shown to impair cell cycle arrest and result in increased tumor cell death, particularly in the absence of intact G1 checkpoints, from loss of p53 and other oncogenetic changes. Normal cells with intact additional checkpoints would be predicted to undergo less cell death. AZD7762 is a potent ATP competitive inhibitor of checkpoint kinases. Early studies on hits obtained from a high throughput screen focussed attention on the critical role of the substitution pattern around the central scaffold in modulating the activity of these inhibitors. Here we report on the optimization of these leads, and describe the structure activity and structure property relationships that led to the discovery of AZD7762 as a highly potent, intravenous potentiating agent for DNA damaging chemotherapies.