Abstract

Evidence suggests that Wnt signalling is downregulated in Alzheimer’s disease (AD), and that this may contribute to pathogenesis through adversely affecting neuronal health and integrity of the blood-brain barrier. Notum is a negative regulator of the Wnt signalling pathway, and we have shown that its expression is upregulated in both a mouse model of AD and in post mortem brain from AD patients. Hence, inhibition of Notum may restore Wnt signalling with potential benefit in AD and other disease where Wnt signalling is compromised. Our objective was to develop a potent, selective and brain penetrant inhibitor of Notum activity suitable for chronic, oral delivery. Such an inhibitor could be administered in rodent models of neurodegenerative disease to determine its role in modulating Wnt signalling. An X ray crystallography screen using the DSPL fragment library was employed to identify diverse, novel hits that bind to the Notum active site. These 61 hits were then profiled in a robust, fluorescence-based enzyme inhibition assay to determine activity (IC50). After further hit development, the chemical matter was triaged to several orthogonal lead series with micromolar affinity. A structure-based drug design process was then used to develop advanced lead molecule ARUK3001185. This presentation will describe the discovery and profile of ARUK3001185.