7PJR

Notum_ARUK3000438

7PJR の概要

• エントリーDOI: 10.2210/pdb7pjr/pdb
• 分子名称: Palmitoleoyl-protein carboxylesterase NOTUM, 2-acetamido-2-deoxy-beta-D-glucopyranose, DIMETHYL SULFOXIDE, ... (6 entities in total)
• 機能のキーワード: notum inhibitor, signaling protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 44576.48

構造登録者

Vecchia, L.,Zhao, Y.,Fish, P.,Jones, E.Y. (登録日: 2021-08-24, 公開日: 2022-09-07, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.51 Å)