A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription

Kenneth Ewan; Bozena Pajak; Mark Stubbs; Helen Todd; Olivier Barbeau; Camilo Quevedo; Hannah Botfield; Rodrigo Young; Ruth Ruddle; Lee Samuel; Alysia Battersby; Florence Raynaud; Nicholas Allen; Stephen Wilson; Branko Latinkic; Paul Workman; Edward McDonald; Julian Blagg; Wynne Aherne; Trevor Dale

doi:10.1158/0008-5472.CAN-10-1028

A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription

Kenneth Ewan, Bozena Pajak, Mark Stubbs, Helen Todd, Olivier Barbeau, Camilo Quevedo, Hannah Botfield, Rodrigo Young, Ruth Ruddle, Lee Samuel, Alysia Battersby, Florence Raynaud, Nicholas Allen, Stephen Wilson, Branko Latinkic, Paul Workman, Edward McDonald, Julian Blagg, Wynne Aherne, Trevor Dale

Research output: Contribution to journal › Article › peer-review

85 Citations (Scopus)

Abstract

The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, beta-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of beta-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors.

Original language	English
Pages (from-to)	5963-73
Number of pages	11
Journal	Cancer Research
Volume	70
Issue number	14
DOIs	https://doi.org/10.1158/0008-5472.CAN-10-1028
Publication status	Published - 15 Jul 2010

Keywords

Animals
Antineoplastic Agents
Cell Line, Tumor
Drug Screening Assays, Antitumor
High-Throughput Screening Assays
Humans
L Cells (Cell Line)
Mice
Signal Transduction
Transcription, Genetic
Wnt Proteins
Xenopus laevis
Zebrafish

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/0008-5472.CAN-10-1028

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Ewan, K., Pajak, B., Stubbs, M., Todd, H., Barbeau, O., Quevedo, C., Botfield, H., Young, R., Ruddle, R., Samuel, L., Battersby, A., Raynaud, F., Allen, N., Wilson, S., Latinkic, B., Workman, P., McDonald, E., Blagg, J., Aherne, W., & Dale, T. (2010). A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription. Cancer Research, 70(14), 5963-73. https://doi.org/10.1158/0008-5472.CAN-10-1028

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abstract = "The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, beta-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of beta-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors.",

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author = "Kenneth Ewan and Bozena Pajak and Mark Stubbs and Helen Todd and Olivier Barbeau and Camilo Quevedo and Hannah Botfield and Rodrigo Young and Ruth Ruddle and Lee Samuel and Alysia Battersby and Florence Raynaud and Nicholas Allen and Stephen Wilson and Branko Latinkic and Paul Workman and Edward McDonald and Julian Blagg and Wynne Aherne and Trevor Dale",

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doi = "10.1158/0008-5472.CAN-10-1028",

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Ewan, K, Pajak, B, Stubbs, M, Todd, H, Barbeau, O, Quevedo, C, Botfield, H, Young, R, Ruddle, R, Samuel, L, Battersby, A, Raynaud, F, Allen, N, Wilson, S, Latinkic, B, Workman, P, McDonald, E, Blagg, J, Aherne, W & Dale, T 2010, 'A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription', Cancer Research, vol. 70, no. 14, pp. 5963-73. https://doi.org/10.1158/0008-5472.CAN-10-1028

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T1 - A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription

AU - Ewan, Kenneth

AU - Pajak, Bozena

AU - Stubbs, Mark

AU - Todd, Helen

AU - Barbeau, Olivier

AU - Quevedo, Camilo

AU - Botfield, Hannah

AU - Young, Rodrigo

AU - Ruddle, Ruth

AU - Samuel, Lee

AU - Battersby, Alysia

AU - Raynaud, Florence

AU - Allen, Nicholas

AU - Wilson, Stephen

AU - Latinkic, Branko

AU - Workman, Paul

AU - McDonald, Edward

AU - Blagg, Julian

AU - Aherne, Wynne

AU - Dale, Trevor

PY - 2010/7/15

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AB - The Wnt signaling pathway is frequently deregulated in cancer due to mutations in genes encoding APC, beta-catenin, and axin. To identify small-molecule inhibitors of Wnt signaling as potential therapeutics, a diverse chemical library was screened using a transcription factor reporter cell line in which the activity of the pathway was induced at the level of Disheveled protein. A series of deconvolution studies was used to focus on three compound series that selectively killed cancer cell lines with constitutive Wnt signaling. Activities of the compounds included the ability to induce degradation of beta-catenin that had been stabilized by a glycogen synthase kinase-3 (GSK-3) inhibitor. This screen illustrates a practical approach to identify small-molecule inhibitors of Wnt signaling that can seed the development of agents suitable to treat patients with Wnt-dependent tumors.

KW - Animals

KW - Antineoplastic Agents

KW - Cell Line, Tumor

KW - Drug Screening Assays, Antitumor

KW - High-Throughput Screening Assays

KW - Humans

KW - L Cells (Cell Line)

KW - Mice

KW - Signal Transduction

KW - Transcription, Genetic

KW - Wnt Proteins

KW - Xenopus laevis

KW - Zebrafish

U2 - 10.1158/0008-5472.CAN-10-1028

DO - 10.1158/0008-5472.CAN-10-1028

M3 - Article

C2 - 20610623

SN - 0008-5472

VL - 70

SP - 5963

EP - 5973

JO - Cancer Research

JF - Cancer Research

IS - 14

ER -

A useful approach to identify novel small-molecule inhibitors of Wnt-dependent transcription

Abstract

Keywords

UN SDGs

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