6R8R

Structure of the Wnt deacylase Notum in complex with isoquinoline 45

6R8R の概要

• エントリーDOI: 10.2210/pdb6r8r/pdb
• 分子名称: Palmitoleoyl-protein carboxylesterase NOTUM, 2-acetamido-2-deoxy-beta-D-glucopyranose, ~{N}-isoquinolin-6-yl-2-(2-methylphenoxy)ethanamide, ... (7 entities in total)
• 機能のキーワード: wnt signalling, notum inhibitor, crystallographic fragment screen, hydrolase
• 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: 45860.54

構造登録者

Vecchia, L.,Zhao, Y.,Ruza, R.R.,Jones, E.Y. (登録日: 2019-04-02, 公開日: 2019-05-08, 最終更新日: 2024-11-06)

主引用文献

Atkinson, B.N.,Steadman, D.,Zhao, Y.,Sipthorp, J.,Vecchia, L.,Ruza, R.R.,Jeganathan, F.,Lines, G.,Frew, S.,Monaghan, A.,Kjær, S.,Bictash, M.,Jones, E.Y.,Fish, P.V.
Discovery of 2-phenoxyacetamides as inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray fragment screen.
Medchemcomm, 10:1361-1369, 2019

PubMed Abstract: NOTUM is a carboxylesterase that has been shown to act by mediating the -depalmitoleoylation of Wnt proteins resulting in suppression of Wnt signaling. Here, we describe the development of NOTUM inhibitors that restore Wnt signaling for use in disease models where NOTUM over activity is an underlying cause. A crystallographic fragment screen with NOTUM identified 2-phenoxyacetamide as binding in the palmitoleate pocket with modest inhibition activity (IC 33 μM). Optimization of hit by SAR studies guided by SBDD identified indazole (IC 0.032 μM) and isoquinoline (IC 0.085 μM) as potent inhibitors of NOTUM. The binding of to NOTUM was rationalized through an X-ray co-crystal structure determination which showed a flipped binding orientation compared to . However, it was not possible to combine NOTUM inhibition activity with metabolic stability as the majority of the compounds tested were rapidly metabolized in an NADPH-independent manner.

PubMed: 31534655
DOI: 10.1039/c9md00096h

実験手法

X-RAY DIFFRACTION (1.27 Å)