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Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics
Whereas recent clinical studies report metastatic melanoma survival rates high as 30–50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773179/ https://www.ncbi.nlm.nih.gov/pubmed/33378376 http://dx.doi.org/10.1371/journal.pone.0243901 |
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author | Cullum, Richard L. Lucas, Lauren M. Senfeld, Jared I. Piazza, John T. Neel, Logan T. Whig, Kanupriya Zhai, Ling Harris, Mackenzie H. Rael, Cristina C. Taylor, Darby C. Cook, Laura J. Kaufmann, David P. Mill, Christopher P. Jacobi, Megan A. Smith, Forrest T. Suto, Mark Bostwick, Robert Gupta, Ram B. David, Allan E. Riese, II, David J. |
author_facet | Cullum, Richard L. Lucas, Lauren M. Senfeld, Jared I. Piazza, John T. Neel, Logan T. Whig, Kanupriya Zhai, Ling Harris, Mackenzie H. Rael, Cristina C. Taylor, Darby C. Cook, Laura J. Kaufmann, David P. Mill, Christopher P. Jacobi, Megan A. Smith, Forrest T. Suto, Mark Bostwick, Robert Gupta, Ram B. David, Allan E. Riese, II, David J. |
author_sort | Cullum, Richard L. |
collection | PubMed |
description | Whereas recent clinical studies report metastatic melanoma survival rates high as 30–50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase. In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2β) functions as a partial agonist at ErbB4. NRG2β/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation. Compounds that exhibit these characteristics likely function as ErbB4 partial agonists, and as such hold promise as therapies for ErbB4-dependent melanomas. Consequently, three highly sensitive and reproducible (Z’ > 0.5) screening assays were developed and deployed for the identification of small-molecule ErbB4 partial agonists. Six compounds were identified that stimulate ErbB4 phosphorylation, fail to stimulate ErbB4-dependent cell proliferation, and appear to selectively inhibit ErbB4-dependent cell proliferation. Whereas further characterization is needed to evaluate the full therapeutic potential of these molecules, this drug discovery platform establishes reliable and scalable approaches for the discovery of ErbB4 inhibitors. |
format | Online Article Text |
id | pubmed-7773179 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-77731792021-01-08 Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics Cullum, Richard L. Lucas, Lauren M. Senfeld, Jared I. Piazza, John T. Neel, Logan T. Whig, Kanupriya Zhai, Ling Harris, Mackenzie H. Rael, Cristina C. Taylor, Darby C. Cook, Laura J. Kaufmann, David P. Mill, Christopher P. Jacobi, Megan A. Smith, Forrest T. Suto, Mark Bostwick, Robert Gupta, Ram B. David, Allan E. Riese, II, David J. PLoS One Research Article Whereas recent clinical studies report metastatic melanoma survival rates high as 30–50%, many tumors remain nonresponsive or become resistant to current therapeutic strategies. Analyses of The Cancer Genome Atlas (TCGA) skin cutaneous melanoma (SKCM) data set suggests that a significant fraction of melanomas potentially harbor gain-of-function mutations in the gene that encodes for the ErbB4 receptor tyrosine kinase. In this work, a drug discovery strategy was developed that is based on the observation that the Q43L mutant of the naturally occurring ErbB4 agonist Neuregulin-2beta (NRG2β) functions as a partial agonist at ErbB4. NRG2β/Q43L stimulates tyrosine phosphorylation, fails to stimulate ErbB4-dependent cell proliferation, and inhibits agonist-induced ErbB4-dependent cell proliferation. Compounds that exhibit these characteristics likely function as ErbB4 partial agonists, and as such hold promise as therapies for ErbB4-dependent melanomas. Consequently, three highly sensitive and reproducible (Z’ > 0.5) screening assays were developed and deployed for the identification of small-molecule ErbB4 partial agonists. Six compounds were identified that stimulate ErbB4 phosphorylation, fail to stimulate ErbB4-dependent cell proliferation, and appear to selectively inhibit ErbB4-dependent cell proliferation. Whereas further characterization is needed to evaluate the full therapeutic potential of these molecules, this drug discovery platform establishes reliable and scalable approaches for the discovery of ErbB4 inhibitors. Public Library of Science 2020-12-30 /pmc/articles/PMC7773179/ /pubmed/33378376 http://dx.doi.org/10.1371/journal.pone.0243901 Text en © 2020 Cullum et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Cullum, Richard L. Lucas, Lauren M. Senfeld, Jared I. Piazza, John T. Neel, Logan T. Whig, Kanupriya Zhai, Ling Harris, Mackenzie H. Rael, Cristina C. Taylor, Darby C. Cook, Laura J. Kaufmann, David P. Mill, Christopher P. Jacobi, Megan A. Smith, Forrest T. Suto, Mark Bostwick, Robert Gupta, Ram B. David, Allan E. Riese, II, David J. Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics |
title | Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics |
title_full | Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics |
title_fullStr | Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics |
title_full_unstemmed | Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics |
title_short | Development and application of high-throughput screens for the discovery of compounds that disrupt ErbB4 signaling: Candidate cancer therapeutics |
title_sort | development and application of high-throughput screens for the discovery of compounds that disrupt erbb4 signaling: candidate cancer therapeutics |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773179/ https://www.ncbi.nlm.nih.gov/pubmed/33378376 http://dx.doi.org/10.1371/journal.pone.0243901 |
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