6R8Q

STRUCTURE OF THE WNT DEACYLASE NOTUM IN COMPLEX WITH A BENZOTRIAZOLE FRAGMENT

Summary for 6R8Q

• Entry DOI: 10.2210/pdb6r8q/pdb
• Descriptor: Palmitoleoyl-protein carboxylesterase NOTUM, 2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (6 entities in total)
• Functional Keywords: wnt signalling, notum inhibitor, crystallographic fragment screen, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 45149.50

Authors

Ruza, R.R.,Vecchia, L.,Jones, E.Y. (deposition date: 2019-04-02, release date: 2019-05-08, Last modification date: 2024-01-24)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.5 Å)