Reactive oxygen species (ROS) are thought to be at the origin of many diseases which are caused by oxidative stress. Tissue injury, organ failure and aging are among the diseases or conditions which are driven by ROS and the importance of oxidative stress as a driver for inflammatory diseases has been appreciated for some time now. The modulation of pathways involved in the responses to oxidative stress is complex and requires a precise understanding of intra-cellular signaling mechanisms. Novel and tractable targets with the potential to be disease modifying have been reported recently in the literature. Inhibition of apoptosis-signaling kinase 1 (ASK1, also known as MAP3K5) has been shown to reduce p38- and JNK-dependent signaling. As such, ASK1 inhibitors have the potential to treat clinically important inflammatory pathologies such as renal, pulmonary and liver diseases, among others. We sought a potent and selective inhibitor of ASK1 suitable for in vivo studies to better understand the therapeutic potential of ASK1 inhibition. Analysis of the ASK1 ATP-binding site suggested a strategy for achieving selectivity for ASK1 versus other kinases which was utilized in the design of an initial library resulting in inhibitors of ASK1 with nanomolar potency. A focused optimization strategy utilizing structure-based design resulted in the identification of exciting ASK1 probe molecules with low nanomolar potency in a cellular assay, high selectivity when tested in kinase and broad pharmacology screening panels, and attractive pharmacokinetic properties. The compounds we describe are attractive tools for in vitro and in vivo studies into the therapeutic potential of ASK1 inhibition.

Highly selective and cell-potent ASK1 inhibitors

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.