7B3I

Notum complex with ARUK3003776

Summary for 7B3I

• Entry DOI: 10.2210/pdb7b3i/pdb
• Descriptor: Palmitoleoyl-protein carboxylesterase NOTUM, SULFATE ION, DIMETHYL SULFOXIDE, ... (6 entities in total)
• Functional Keywords: notum inhibitor, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 44938.91

Authors

Zhao, Y.,Jones, E.Y.,Fish, P. (deposition date: 2020-12-01, release date: 2021-12-08, Last modification date: 2024-02-07)

Primary citation

Steadman, D.,Atkinson, B.N.,Zhao, Y.,Willis, N.J.,Frew, S.,Monaghan, A.,Patel, C.,Armstrong, E.,Costelloe, K.,Magno, L.,Bictash, M.,Jones, E.Y.,Fish, P.V.,Svensson, F.
Virtual Screening Directly Identifies New Fragment-Sized Inhibitors of Carboxylesterase Notum with Nanomolar Activity.
J.Med.Chem., 65:562-578, 2022

PubMed Abstract: Notum is a negative regulator of Wnt signaling acting through the hydrolysis of a palmitoleoylate ester, which is required for Wnt activity. Inhibitors of Notum could be of use in diseases where dysfunctional Notum activity is an underlying cause. A docking-based virtual screen (VS) of a large commercial library was used to shortlist 952 compounds for experimental validation as inhibitors of Notum. The VS was successful with 31 compounds having an IC < 500 nM. A critical selection process was then applied with two clusters and two singletons (-) selected for hit validation. Optimization of guided by structural biology identified potent inhibitors of Notum activity that restored Wnt/β-catenin signaling in cell-based models. The [1,2,4]triazolo[4,3-]pyradizin-3(2)-one series represent a new chemical class of Notum inhibitors and the first to be discovered by a VS campaign. These results demonstrate the value of VS with well-designed docking models based on X-ray structures.

PubMed: 34939789
DOI: 10.1021/acs.jmedchem.1c01735

Experimental method

X-RAY DIFFRACTION (1.34 Å)