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Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo
Recently, the targeting of ERK with ATP-competitive inhibitors has emerged as a potential clinical strategy to overcome acquired resistance to BRAF and MEK inhibitor combination therapies. In this study, we investigate an alternative strategy of targeting the D-recruitment site (DRS) of ERK. The DRS...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863825/ https://www.ncbi.nlm.nih.gov/pubmed/31745079 http://dx.doi.org/10.1038/s41467-019-12996-8 |
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author | Kaoud, Tamer S. Johnson, William H. Ebelt, Nancy D. Piserchio, Andrea Zamora-Olivares, Diana Van Ravenstein, Sabrina X. Pridgen, Jacey R. Edupuganti, Ramakrishna Sammons, Rachel Cano, Micael Warthaka, Mangalika Harger, Matthew Tavares, Clint D. J. Park, Jihyun Radwan, Mohamed F. Ren, Pengyu Anslyn, Eric V. Tsai, Kenneth Y. Ghose, Ranajeet Dalby, Kevin N. |
author_facet | Kaoud, Tamer S. Johnson, William H. Ebelt, Nancy D. Piserchio, Andrea Zamora-Olivares, Diana Van Ravenstein, Sabrina X. Pridgen, Jacey R. Edupuganti, Ramakrishna Sammons, Rachel Cano, Micael Warthaka, Mangalika Harger, Matthew Tavares, Clint D. J. Park, Jihyun Radwan, Mohamed F. Ren, Pengyu Anslyn, Eric V. Tsai, Kenneth Y. Ghose, Ranajeet Dalby, Kevin N. |
author_sort | Kaoud, Tamer S. |
collection | PubMed |
description | Recently, the targeting of ERK with ATP-competitive inhibitors has emerged as a potential clinical strategy to overcome acquired resistance to BRAF and MEK inhibitor combination therapies. In this study, we investigate an alternative strategy of targeting the D-recruitment site (DRS) of ERK. The DRS is a conserved region that lies distal to the active site and mediates ERK–protein interactions. We demonstrate that the small molecule BI-78D3 binds to the DRS of ERK2 and forms a covalent adduct with a conserved cysteine residue (C159) within the pocket and disrupts signaling in vivo. BI-78D3 does not covalently modify p38MAPK, JNK or ERK5. BI-78D3 promotes apoptosis in BRAF inhibitor-naive and resistant melanoma cells containing a BRAF V600E mutation. These studies provide the basis for designing modulators of protein–protein interactions involving ERK, with the potential to impact ERK signaling dynamics and to induce cell cycle arrest and apoptosis in ERK-dependent cancers. |
format | Online Article Text |
id | pubmed-6863825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68638252019-11-21 Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo Kaoud, Tamer S. Johnson, William H. Ebelt, Nancy D. Piserchio, Andrea Zamora-Olivares, Diana Van Ravenstein, Sabrina X. Pridgen, Jacey R. Edupuganti, Ramakrishna Sammons, Rachel Cano, Micael Warthaka, Mangalika Harger, Matthew Tavares, Clint D. J. Park, Jihyun Radwan, Mohamed F. Ren, Pengyu Anslyn, Eric V. Tsai, Kenneth Y. Ghose, Ranajeet Dalby, Kevin N. Nat Commun Article Recently, the targeting of ERK with ATP-competitive inhibitors has emerged as a potential clinical strategy to overcome acquired resistance to BRAF and MEK inhibitor combination therapies. In this study, we investigate an alternative strategy of targeting the D-recruitment site (DRS) of ERK. The DRS is a conserved region that lies distal to the active site and mediates ERK–protein interactions. We demonstrate that the small molecule BI-78D3 binds to the DRS of ERK2 and forms a covalent adduct with a conserved cysteine residue (C159) within the pocket and disrupts signaling in vivo. BI-78D3 does not covalently modify p38MAPK, JNK or ERK5. BI-78D3 promotes apoptosis in BRAF inhibitor-naive and resistant melanoma cells containing a BRAF V600E mutation. These studies provide the basis for designing modulators of protein–protein interactions involving ERK, with the potential to impact ERK signaling dynamics and to induce cell cycle arrest and apoptosis in ERK-dependent cancers. Nature Publishing Group UK 2019-11-19 /pmc/articles/PMC6863825/ /pubmed/31745079 http://dx.doi.org/10.1038/s41467-019-12996-8 Text en © The Author(s) 2019 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 Kaoud, Tamer S. Johnson, William H. Ebelt, Nancy D. Piserchio, Andrea Zamora-Olivares, Diana Van Ravenstein, Sabrina X. Pridgen, Jacey R. Edupuganti, Ramakrishna Sammons, Rachel Cano, Micael Warthaka, Mangalika Harger, Matthew Tavares, Clint D. J. Park, Jihyun Radwan, Mohamed F. Ren, Pengyu Anslyn, Eric V. Tsai, Kenneth Y. Ghose, Ranajeet Dalby, Kevin N. Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo |
title | Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo |
title_full | Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo |
title_fullStr | Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo |
title_full_unstemmed | Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo |
title_short | Modulating multi-functional ERK complexes by covalent targeting of a recruitment site in vivo |
title_sort | modulating multi-functional erk complexes by covalent targeting of a recruitment site in vivo |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863825/ https://www.ncbi.nlm.nih.gov/pubmed/31745079 http://dx.doi.org/10.1038/s41467-019-12996-8 |
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