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Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity

Atkinson, Benjamin N; Willis, Nicky J; Zhao, Yuguang; Patel, Chandni; Frew, Sarah; Costelloe, Kathryn; Magno, Lorenza; ... Fish, Paul V; + view all (2023) Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity. European Journal of Medicinal Chemistry , 251 , Article 115132. 10.1016/j.ejmech.2023.115132. Green open access

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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.

Type: Article
Title: Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ejmech.2023.115132
Publisher version: https://doi.org/10.1016/j.ejmech.2023.115132
Language: English
Additional information: Copyright © 2023 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: acyl Indolines, Covalent inhibition, Notum inhibitors, Structural biology, Wnt signaling
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10164409
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