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Mutant-selective degradation by BRAF-targeting PROTACs
Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new t...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876048/ https://www.ncbi.nlm.nih.gov/pubmed/33568647 http://dx.doi.org/10.1038/s41467-021-21159-7 |
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author | Alabi, Shanique Jaime-Figueroa, Saul Yao, Zhan Gao, Yijun Hines, John Samarasinghe, Kusal T. G. Vogt, Lea Rosen, Neal Crews, Craig M. |
author_facet | Alabi, Shanique Jaime-Figueroa, Saul Yao, Zhan Gao, Yijun Hines, John Samarasinghe, Kusal T. G. Vogt, Lea Rosen, Neal Crews, Craig M. |
author_sort | Alabi, Shanique |
collection | PubMed |
description | Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAF(WT) is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAF(WT) sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAF(WT), providing an anti-tumor drug modality that expands the therapeutic window. |
format | Online Article Text |
id | pubmed-7876048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-78760482021-02-24 Mutant-selective degradation by BRAF-targeting PROTACs Alabi, Shanique Jaime-Figueroa, Saul Yao, Zhan Gao, Yijun Hines, John Samarasinghe, Kusal T. G. Vogt, Lea Rosen, Neal Crews, Craig M. Nat Commun Article Over 300 BRAF missense mutations have been identified in patients, yet currently approved drugs target V600 mutants alone. Moreover, acquired resistance inevitably emerges, primarily due to RAF lesions that prevent inhibition of BRAF V600 with current treatments. Therefore, there is a need for new therapies that target other mechanisms of activated BRAF. In this study, we use the Proteolysis Targeting Chimera (PROTAC) technology, which promotes ubiquitination and degradation of neo-substrates, to address the limitations of BRAF inhibitor-based therapies. Using vemurafenib-based PROTACs, we achieve low nanomolar degradation of all classes of BRAF mutants, but spare degradation of WT RAF family members. Our lead PROTAC outperforms vemurafenib in inhibiting cancer cell growth and shows in vivo efficacy in a Class 2 BRAF xenograft model. Mechanistic studies reveal that BRAF(WT) is spared due to weak ternary complex formation in cells owing to its quiescent inactivated conformation, and activation of BRAF(WT) sensitizes it to degradation. This study highlights the degree of selectivity achievable with degradation-based approaches by targeting mutant BRAF-driven cancers while sparing BRAF(WT), providing an anti-tumor drug modality that expands the therapeutic window. Nature Publishing Group UK 2021-02-10 /pmc/articles/PMC7876048/ /pubmed/33568647 http://dx.doi.org/10.1038/s41467-021-21159-7 Text en © The Author(s) 2021 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Alabi, Shanique Jaime-Figueroa, Saul Yao, Zhan Gao, Yijun Hines, John Samarasinghe, Kusal T. G. Vogt, Lea Rosen, Neal Crews, Craig M. Mutant-selective degradation by BRAF-targeting PROTACs |
title | Mutant-selective degradation by BRAF-targeting PROTACs |
title_full | Mutant-selective degradation by BRAF-targeting PROTACs |
title_fullStr | Mutant-selective degradation by BRAF-targeting PROTACs |
title_full_unstemmed | Mutant-selective degradation by BRAF-targeting PROTACs |
title_short | Mutant-selective degradation by BRAF-targeting PROTACs |
title_sort | mutant-selective degradation by braf-targeting protacs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876048/ https://www.ncbi.nlm.nih.gov/pubmed/33568647 http://dx.doi.org/10.1038/s41467-021-21159-7 |
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