8BT2

Notum Inhibitor ARUK3004876

Summary for 8BT2

• Entry DOI: 10.2210/pdb8bt2/pdb
• Descriptor: Palmitoleoyl-protein carboxylesterase NOTUM, 2-acetamido-2-deoxy-beta-D-glucopyranose, SULFATE ION, ... (7 entities in total)
• Functional Keywords: inhibitor notum, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 44886.79

Authors

Zhao, Y.,Jones, E.Y.,Fish, P. (deposition date: 2022-11-27, release date: 2022-12-14, Last modification date: 2024-11-06)

Primary citation

Atkinson, B.N.,Willis, N.J.,Zhao, Y.,Patel, C.,Frew, S.,Costelloe, K.,Magno, L.,Svensson, F.,Jones, E.Y.,Fish, P.V.
Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity.
Eur.J.Med.Chem., 251:115132-115132, 2023

PubMed Abstract: N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.

PubMed: 36934521
DOI: 10.1016/j.ejmech.2023.115132

Experimental method

X-RAY DIFFRACTION (1.7 Å)