7PKV

Notum_Inhibitor ARUK3000223

Summary for 7PKV

• Entry DOI: 10.2210/pdb7pkv/pdb
• Descriptor: Palmitoleoyl-protein carboxylesterase NOTUM, SULFATE ION, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: notum inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 44720.50

Authors

Ruza, R.,Zhao, Y.,Fish, P.,Jones, E.Y. (deposition date: 2021-08-26, release date: 2022-09-07, Last modification date: 2024-11-06)

Primary citation

Willis, N.J.,Mahy, W.,Sipthorp, J.,Zhao, Y.,Woodward, H.L.,Atkinson, B.N.,Bayle, E.D.,Svensson, F.,Frew, S.,Jeganathan, F.,Monaghan, A.,Benvegnu, S.,Jolly, S.,Vecchia, L.,Ruza, R.R.,Kjaer, S.,Howell, S.,Snijders, A.P.,Bictash, M.,Salinas, P.C.,Vincent, J.P.,Jones, E.Y.,Whiting, P.,Fish, P.V.
Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit.
J.Med.Chem., 65:7212-7230, 2022

PubMed Abstract: 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 (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 and as a pair of outstanding hits. Fragment development of delivered that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed to be selective against serine hydrolases, kinases, and drug targets.

PubMed: 35536179
DOI: 10.1021/acs.jmedchem.2c00162

Experimental method

X-RAY DIFFRACTION (1.68 Å)