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Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds
Oncogenic RAS proteins are important for driving tumour formation, and for maintenance of the transformed phenotype, and thus their relevance as a cancer therapeutic target is undeniable. We focused here on obtaining peptidomimetics, which have good pharmacological properties, to block Ras–effector...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499927/ https://www.ncbi.nlm.nih.gov/pubmed/36138080 http://dx.doi.org/10.1038/s41598-022-19703-6 |
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author | Pallara, Chiara Cabot, Debora Rivas, Josep Brun, Sonia Seco, Jesús Abuasaker, Baraa Tarragó, Teresa Jaumot, Montserrat Prades, Roger Agell, Neus |
author_facet | Pallara, Chiara Cabot, Debora Rivas, Josep Brun, Sonia Seco, Jesús Abuasaker, Baraa Tarragó, Teresa Jaumot, Montserrat Prades, Roger Agell, Neus |
author_sort | Pallara, Chiara |
collection | PubMed |
description | Oncogenic RAS proteins are important for driving tumour formation, and for maintenance of the transformed phenotype, and thus their relevance as a cancer therapeutic target is undeniable. We focused here on obtaining peptidomimetics, which have good pharmacological properties, to block Ras–effector interaction. Computational analysis was used to identify hot spots of RAS relevant for these interactions and to screen a library of peptidomimetics. Nine compounds were synthesized and assayed for their activity as RAS inhibitors in cultured cells. Most of them induced a reduction in ERK and AKT activation by EGF, a marker of RAS activity. The most potent inhibitor disrupted Raf and PI3K interaction with oncogenic KRAS, corroborating its mechanism of action as an inhibitor of protein–protein interactions, and thus validating our computational methodology. Most interestingly, improvement of one of the compounds allowed us to obtain a peptidomimetic that decreased the survival of pancreatic cancer cell lines harbouring oncogenic KRAS. |
format | Online Article Text |
id | pubmed-9499927 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-94999272022-09-24 Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds Pallara, Chiara Cabot, Debora Rivas, Josep Brun, Sonia Seco, Jesús Abuasaker, Baraa Tarragó, Teresa Jaumot, Montserrat Prades, Roger Agell, Neus Sci Rep Article Oncogenic RAS proteins are important for driving tumour formation, and for maintenance of the transformed phenotype, and thus their relevance as a cancer therapeutic target is undeniable. We focused here on obtaining peptidomimetics, which have good pharmacological properties, to block Ras–effector interaction. Computational analysis was used to identify hot spots of RAS relevant for these interactions and to screen a library of peptidomimetics. Nine compounds were synthesized and assayed for their activity as RAS inhibitors in cultured cells. Most of them induced a reduction in ERK and AKT activation by EGF, a marker of RAS activity. The most potent inhibitor disrupted Raf and PI3K interaction with oncogenic KRAS, corroborating its mechanism of action as an inhibitor of protein–protein interactions, and thus validating our computational methodology. Most interestingly, improvement of one of the compounds allowed us to obtain a peptidomimetic that decreased the survival of pancreatic cancer cell lines harbouring oncogenic KRAS. Nature Publishing Group UK 2022-09-22 /pmc/articles/PMC9499927/ /pubmed/36138080 http://dx.doi.org/10.1038/s41598-022-19703-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Pallara, Chiara Cabot, Debora Rivas, Josep Brun, Sonia Seco, Jesús Abuasaker, Baraa Tarragó, Teresa Jaumot, Montserrat Prades, Roger Agell, Neus Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds |
title | Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds |
title_full | Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds |
title_fullStr | Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds |
title_full_unstemmed | Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds |
title_short | Peptidomimetics designed to bind to RAS effector domain are promising cancer therapeutic compounds |
title_sort | peptidomimetics designed to bind to ras effector domain are promising cancer therapeutic compounds |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9499927/ https://www.ncbi.nlm.nih.gov/pubmed/36138080 http://dx.doi.org/10.1038/s41598-022-19703-6 |
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