Biophysical survey of small-molecule β-catenin inhibitors: a cautionary tale
Biophysical survey of small-molecule β-catenin inhibitors: a cautionary tale
The canonical Wingless-related integration site signaling pathway plays a critical role in human physiology, and its dysregulation can lead to an array of diseases. β-Catenin is a multifunctional protein within this pathway and an attractive yet challenging therapeutic target, most notably in oncology. This has stimulated the search for potent small-molecule inhibitors binding directly to the β-catenin surface to inhibit its protein-protein interactions and downstream signaling. Here, we provide an account of the claimed (and some putative) small-molecule ligands of β-catenin from the literature. Through in silico analysis, we show that most of these molecules contain promiscuous chemical substructures notorious for interfering with screening assays. Finally, and in line with this analysis, we demonstrate using orthogonal biophysical techniques that none of the examined small molecules bind at the surface of β-catenin. While shedding doubts on their reported mode of action, this study also reaffirms β-catenin as a prominent target in drug discovery.
Animals, Biophysical Phenomena, Drug Discovery, Humans, Small Molecule Libraries/chemistry, Wnt Signaling Pathway, beta Catenin
7246–7261
McCoy, Michael, Arron
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Spicer, Dominique
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Wells, Neil J.
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Hoogewijs, Kurt
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Fiedler, Marc
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Baud, Matthias G.J.
8752d519-3d33-43b6-9a77-ab731d410c2e
26 May 2022
McCoy, Michael, Arron
151681b5-f1e3-4ace-83ae-adc2755f9af9
Spicer, Dominique
ae9b45be-f4ba-4cb7-a349-29008c02e60b
Wells, Neil J.
86312185-007b-495b-86da-4e2e5b9b8025
Hoogewijs, Kurt
c51306b4-5e39-4e73-bd66-2f7220e07316
Fiedler, Marc
52f2a138-d777-4222-b3e1-d67f6d117d93
Baud, Matthias G.J.
8752d519-3d33-43b6-9a77-ab731d410c2e
McCoy, Michael, Arron, Spicer, Dominique, Wells, Neil J., Hoogewijs, Kurt, Fiedler, Marc and Baud, Matthias G.J.
(2022)
Biophysical survey of small-molecule β-catenin inhibitors: a cautionary tale.
Journal of Medicinal Chemistry, 65 (10), .
(doi:10.1021/acs.jmedchem.2c00228).
Abstract
The canonical Wingless-related integration site signaling pathway plays a critical role in human physiology, and its dysregulation can lead to an array of diseases. β-Catenin is a multifunctional protein within this pathway and an attractive yet challenging therapeutic target, most notably in oncology. This has stimulated the search for potent small-molecule inhibitors binding directly to the β-catenin surface to inhibit its protein-protein interactions and downstream signaling. Here, we provide an account of the claimed (and some putative) small-molecule ligands of β-catenin from the literature. Through in silico analysis, we show that most of these molecules contain promiscuous chemical substructures notorious for interfering with screening assays. Finally, and in line with this analysis, we demonstrate using orthogonal biophysical techniques that none of the examined small molecules bind at the surface of β-catenin. While shedding doubts on their reported mode of action, this study also reaffirms β-catenin as a prominent target in drug discovery.
Text
acs.jmedchem.2c00228
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e-pub ahead of print date: 17 May 2022
Published date: 26 May 2022
Additional Information:
Funding Information:
This work is supported by awards to M.B. from the Wessex Medical Research and the Rosetrees Trust (grants A1459 and M653). NMR and mass spectrometry facilities in Southampton are supported by the EPSRC core capability award (EP/K039466/1). M.F. is supported by the Medical Research Council (grant MC_U105192713 to M. Bienz). K.H. is supported by the FWO and the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant no 665501) and a Fonds Wetenschappelijk Onderzoek-Vlaanderen research grant (2018, 1.5.193.18N).
Funding Information:
This work is supported by awards to M.B. from the Wessex Medical Research and the Rosetrees Trust (grants A1459 and M653). NMR and mass spectrometry facilities in Southampton are supported by the EPSRC core capability award (EP/K039466/1). M.F. is supported by the Medical Research Council (grant MC_U105192713 to M. Bienz). K.H. is supported by the FWO and the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie (grant no 665501) and a Fonds Wetenschappelijk Onderzoek-Vlaanderen research grant (2018, 1.5.193.18N).
Publisher Copyright:
© 2022 American Chemical Society.
Keywords:
Animals, Biophysical Phenomena, Drug Discovery, Humans, Small Molecule Libraries/chemistry, Wnt Signaling Pathway, beta Catenin
Identifiers
Local EPrints ID: 458128
URI: http://eprints.soton.ac.uk/id/eprint/458128
ISSN: 0022-2623
PURE UUID: 0dab8b7f-3c4b-4091-a2bf-dc742e20c85a
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Date deposited: 28 Jun 2022 17:36
Last modified: 17 Mar 2024 03:41
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Author:
Michael, Arron McCoy
Author:
Dominique Spicer
Author:
Kurt Hoogewijs
Author:
Marc Fiedler
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