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A small molecule inhibitor of HER3: a proof-of-concept study
Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489893/ https://www.ncbi.nlm.nih.gov/pubmed/32815546 http://dx.doi.org/10.1042/BCJ20200496 |
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author | Colomba, Audrey Fitzek, Martina George, Roger Weitsman, Gregory Roberts, Selene Zanetti-Domingues, Laura Hirsch, Michael Rolfe, Daniel J. Mehmood, Shahid Madin, Andrew Claus, Jeroen Kjaer, Svend Snijders, Ambrosius P. Ng, Tony Martin-Fernandez, Marisa Smith, David M. Parker, Peter J. |
author_facet | Colomba, Audrey Fitzek, Martina George, Roger Weitsman, Gregory Roberts, Selene Zanetti-Domingues, Laura Hirsch, Michael Rolfe, Daniel J. Mehmood, Shahid Madin, Andrew Claus, Jeroen Kjaer, Svend Snijders, Ambrosius P. Ng, Tony Martin-Fernandez, Marisa Smith, David M. Parker, Peter J. |
author_sort | Colomba, Audrey |
collection | PubMed |
description | Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore. As a well-known allosteric activator of epidermal growth factor receptor family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium-throughput thermal shift assay screening strategy to assess over 100 000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2–HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2–HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases. |
format | Online Article Text |
id | pubmed-7489893 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74898932020-09-22 A small molecule inhibitor of HER3: a proof-of-concept study Colomba, Audrey Fitzek, Martina George, Roger Weitsman, Gregory Roberts, Selene Zanetti-Domingues, Laura Hirsch, Michael Rolfe, Daniel J. Mehmood, Shahid Madin, Andrew Claus, Jeroen Kjaer, Svend Snijders, Ambrosius P. Ng, Tony Martin-Fernandez, Marisa Smith, David M. Parker, Peter J. Biochem J Cancer Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore. As a well-known allosteric activator of epidermal growth factor receptor family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium-throughput thermal shift assay screening strategy to assess over 100 000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2–HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2–HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases. Portland Press Ltd. 2020-09-18 2020-09-10 /pmc/articles/PMC7489893/ /pubmed/32815546 http://dx.doi.org/10.1042/BCJ20200496 Text en © 2020 The Author(s) https://creativecommons.org/licenses/by/4.0/ This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . Open access for this article was enabled by the participation of The Francis Crick Institute in an all-inclusive Read & Publish pilot with Portland Press and the Biochemical Society under a transformative agreement with JISC. |
spellingShingle | Cancer Colomba, Audrey Fitzek, Martina George, Roger Weitsman, Gregory Roberts, Selene Zanetti-Domingues, Laura Hirsch, Michael Rolfe, Daniel J. Mehmood, Shahid Madin, Andrew Claus, Jeroen Kjaer, Svend Snijders, Ambrosius P. Ng, Tony Martin-Fernandez, Marisa Smith, David M. Parker, Peter J. A small molecule inhibitor of HER3: a proof-of-concept study |
title | A small molecule inhibitor of HER3: a proof-of-concept study |
title_full | A small molecule inhibitor of HER3: a proof-of-concept study |
title_fullStr | A small molecule inhibitor of HER3: a proof-of-concept study |
title_full_unstemmed | A small molecule inhibitor of HER3: a proof-of-concept study |
title_short | A small molecule inhibitor of HER3: a proof-of-concept study |
title_sort | small molecule inhibitor of her3: a proof-of-concept study |
topic | Cancer |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489893/ https://www.ncbi.nlm.nih.gov/pubmed/32815546 http://dx.doi.org/10.1042/BCJ20200496 |
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