Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit
By N. Willis, W. Mahy, James Sipthorp, Yuguang Zhao, H. Woodward, Benjamin N. Atkinson, Elliott D Bayle, Fredrik Svensson, S. Frew, F. Jeganathan and 14 more. 2022
13 citations recorded by the source corpus.
Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer’s disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets.
Subfields: Computational Theory and Mathematics, Molecular Biology
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In Molecular Biology
Citations in the corpus
- Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity (2023, methodology): “Selected compounds were routinely screened for aqueous solubility in PBS (pH 7.4), transit performance in MDCK-MDR1 cell lines for permeability, and metabolic stability in MLM and HLM as a measure of clearance [21,29].”