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Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S)
Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mu...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9596369/ https://www.ncbi.nlm.nih.gov/pubmed/35864332 http://dx.doi.org/10.1038/s41589-022-01065-9 |
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author | Zhang, Ziyang Guiley, Keelan Z. Shokat, Kevan M. |
author_facet | Zhang, Ziyang Guiley, Keelan Z. Shokat, Kevan M. |
author_sort | Zhang, Ziyang |
collection | PubMed |
description | Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines. [Image: see text] |
format | Online Article Text |
id | pubmed-9596369 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-95963692022-10-27 Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S) Zhang, Ziyang Guiley, Keelan Z. Shokat, Kevan M. Nat Chem Biol Article Drugs that directly impede the function of driver oncogenes offer exceptional efficacy and a therapeutic window. The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point. KRAS is the most frequently mutated proto-oncogene in human cancer, yet despite success targeting the G12C allele, targeted therapy for other hotspot mutants of KRAS has not been described. Here we report the discovery of small molecules that covalently target a G12S somatic mutation in K-Ras and suppress its oncogenic signaling. We show that these molecules are active in cells expressing K-Ras(G12S) but spare the wild-type protein. Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines. [Image: see text] Nature Publishing Group US 2022-07-21 2022 /pmc/articles/PMC9596369/ /pubmed/35864332 http://dx.doi.org/10.1038/s41589-022-01065-9 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 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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Zhang, Ziyang Guiley, Keelan Z. Shokat, Kevan M. Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S) |
title | Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S) |
title_full | Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S) |
title_fullStr | Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S) |
title_full_unstemmed | Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S) |
title_short | Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S) |
title_sort | chemical acylation of an acquired serine suppresses oncogenic signaling of k-ras(g12s) |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9596369/ https://www.ncbi.nlm.nih.gov/pubmed/35864332 http://dx.doi.org/10.1038/s41589-022-01065-9 |
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