Checkpoint kinase 1 (Chk1) is a serine/threonine kinase which functions as a central mediator of the S and G2/M phase cell cycle checkpoints, blocking the G2/M transition to allow for repair of damaged DNA. Inhibition of Chk1 is an emerging strategy for selectively potentiating the cytotoxicity of chemotherapeutic agents in checkpoint defective tumor cells while minimizing toxicity to normal, checkpoint competent cells.We have previously described how the application of structure-based design to a low micromolar potency hit series from a high throughput screening campaign resulted in the evolution of the novel and potent 1,7-diazacarbazole class of inhibitors of Chk1. Initial 1,7-diazacarbazole leads demonstrated encouraging rodent pharmacokinetic properties, including high oral bioavailability. However significant undesirable activities versus both kinase and non-kinase off-targets were identified. We will describe how through a series of SAR investigations we were able to optimize biochemical potency and identify the structural features responsible for these liabilities. Subsequently we were able to transition to a new series with improved physical properties, notably reduced lipophilicity, leading to a greatly improved off-target profile and ultimately a clinical candidate.

Lead optimization in the 1,7-diazacarbazole class of inhibitors of checkpoint kinase 1

248th National Meeting (2014)

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