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Inhibitors of BRAF dimers using an allosteric site

BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAF(V600E) signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which...

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Autores principales: Cotto-Rios, Xiomaris M., Agianian, Bogos, Gitego, Nadege, Zacharioudakis, Emmanouil, Giricz, Orsi, Wu, Yang, Zou, Yiyu, Verma, Amit, Poulikakos, Poulikos I., Gavathiotis, Evripidis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462985/
https://www.ncbi.nlm.nih.gov/pubmed/32873792
http://dx.doi.org/10.1038/s41467-020-18123-2
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author Cotto-Rios, Xiomaris M.
Agianian, Bogos
Gitego, Nadege
Zacharioudakis, Emmanouil
Giricz, Orsi
Wu, Yang
Zou, Yiyu
Verma, Amit
Poulikakos, Poulikos I.
Gavathiotis, Evripidis
author_facet Cotto-Rios, Xiomaris M.
Agianian, Bogos
Gitego, Nadege
Zacharioudakis, Emmanouil
Giricz, Orsi
Wu, Yang
Zou, Yiyu
Verma, Amit
Poulikakos, Poulikos I.
Gavathiotis, Evripidis
author_sort Cotto-Rios, Xiomaris M.
collection PubMed
description BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAF(V600E) signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors.
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spelling pubmed-74629852020-09-16 Inhibitors of BRAF dimers using an allosteric site Cotto-Rios, Xiomaris M. Agianian, Bogos Gitego, Nadege Zacharioudakis, Emmanouil Giricz, Orsi Wu, Yang Zou, Yiyu Verma, Amit Poulikakos, Poulikos I. Gavathiotis, Evripidis Nat Commun Article BRAF kinase, a critical effector of the ERK signaling pathway, is hyperactivated in many cancers. Oncogenic BRAF(V600E) signals as an active monomer in the absence of active RAS, however, in many tumors BRAF dimers mediate ERK signaling. FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which leads to tumor resistance. We found that Ponatinib, an FDA-approved drug, is an effective inhibitor of BRAF monomers and dimers. Ponatinib binds the BRAF dimer and stabilizes a distinct αC-helix conformation through interaction with a previously unrevealed allosteric site. Using these structural insights, we developed PHI1, a BRAF inhibitor that fully uncovers the allosteric site. PHI1 exhibits discrete cellular selectivity for BRAF dimers, with enhanced inhibition of the second protomer when the first protomer is occupied, comprising a novel class of dimer selective inhibitors. This work shows that Ponatinib and BRAF dimer selective inhibitors will be useful in treating BRAF-dependent tumors. Nature Publishing Group UK 2020-09-01 /pmc/articles/PMC7462985/ /pubmed/32873792 http://dx.doi.org/10.1038/s41467-020-18123-2 Text en © The Author(s) 2020 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
Cotto-Rios, Xiomaris M.
Agianian, Bogos
Gitego, Nadege
Zacharioudakis, Emmanouil
Giricz, Orsi
Wu, Yang
Zou, Yiyu
Verma, Amit
Poulikakos, Poulikos I.
Gavathiotis, Evripidis
Inhibitors of BRAF dimers using an allosteric site
title Inhibitors of BRAF dimers using an allosteric site
title_full Inhibitors of BRAF dimers using an allosteric site
title_fullStr Inhibitors of BRAF dimers using an allosteric site
title_full_unstemmed Inhibitors of BRAF dimers using an allosteric site
title_short Inhibitors of BRAF dimers using an allosteric site
title_sort inhibitors of braf dimers using an allosteric site
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462985/
https://www.ncbi.nlm.nih.gov/pubmed/32873792
http://dx.doi.org/10.1038/s41467-020-18123-2
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