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Eliminating oncogenic RAS: back to the future at the drawing board
RAS drug development has made enormous strides in the past ten years, with the first direct KRAS inhibitor being approved in 2021. However, despite the clinical success of covalent KRAS-G12C inhibitors, we are immediately confronted with resistances as commonly found with targeted drugs. Previously...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9987992/ https://www.ncbi.nlm.nih.gov/pubmed/36688434 http://dx.doi.org/10.1042/BST20221343 |
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author | Steffen, Candy Laura Kaya, Pelin Schaffner-Reckinger, Elisabeth Abankwa, Daniel |
author_facet | Steffen, Candy Laura Kaya, Pelin Schaffner-Reckinger, Elisabeth Abankwa, Daniel |
author_sort | Steffen, Candy Laura |
collection | PubMed |
description | RAS drug development has made enormous strides in the past ten years, with the first direct KRAS inhibitor being approved in 2021. However, despite the clinical success of covalent KRAS-G12C inhibitors, we are immediately confronted with resistances as commonly found with targeted drugs. Previously believed to be undruggable due to its lack of obvious druggable pockets, a couple of new approaches to hit this much feared oncogene have now been carved out. We here concisely review these approaches to directly target four druggable sites of RAS from various angles. Our analysis focuses on the lessons learnt during the development of allele-specific covalent and non-covalent RAS inhibitors, the potential of macromolecular binders to facilitate the discovery and validation of targetable sites on RAS and finally an outlook on a future that may engage more small molecule binders to become drugs. We foresee that the latter could happen mainly in two ways: First, non-covalent small molecule inhibitors may be derived from the development of covalent binders. Second, reversible small molecule binders could be utilized for novel targeting modalities, such as degraders of RAS. Provided that degraders eliminate RAS by recruiting differentially expressed E3-ligases, this approach could enable unprecedented tissue- or developmental stage-specific destruction of RAS with potential advantages for on-target toxicity. We conclude that novel creative ideas continue to be important to exterminate RAS in cancer and other RAS pathway-driven diseases, such as RASopathies. |
format | Online Article Text |
id | pubmed-9987992 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-99879922023-03-07 Eliminating oncogenic RAS: back to the future at the drawing board Steffen, Candy Laura Kaya, Pelin Schaffner-Reckinger, Elisabeth Abankwa, Daniel Biochem Soc Trans Review Articles RAS drug development has made enormous strides in the past ten years, with the first direct KRAS inhibitor being approved in 2021. However, despite the clinical success of covalent KRAS-G12C inhibitors, we are immediately confronted with resistances as commonly found with targeted drugs. Previously believed to be undruggable due to its lack of obvious druggable pockets, a couple of new approaches to hit this much feared oncogene have now been carved out. We here concisely review these approaches to directly target four druggable sites of RAS from various angles. Our analysis focuses on the lessons learnt during the development of allele-specific covalent and non-covalent RAS inhibitors, the potential of macromolecular binders to facilitate the discovery and validation of targetable sites on RAS and finally an outlook on a future that may engage more small molecule binders to become drugs. We foresee that the latter could happen mainly in two ways: First, non-covalent small molecule inhibitors may be derived from the development of covalent binders. Second, reversible small molecule binders could be utilized for novel targeting modalities, such as degraders of RAS. Provided that degraders eliminate RAS by recruiting differentially expressed E3-ligases, this approach could enable unprecedented tissue- or developmental stage-specific destruction of RAS with potential advantages for on-target toxicity. We conclude that novel creative ideas continue to be important to exterminate RAS in cancer and other RAS pathway-driven diseases, such as RASopathies. Portland Press Ltd. 2023-02-27 2023-01-23 /pmc/articles/PMC9987992/ /pubmed/36688434 http://dx.doi.org/10.1042/BST20221343 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Review Articles Steffen, Candy Laura Kaya, Pelin Schaffner-Reckinger, Elisabeth Abankwa, Daniel Eliminating oncogenic RAS: back to the future at the drawing board |
title | Eliminating oncogenic RAS: back to the future at the drawing board |
title_full | Eliminating oncogenic RAS: back to the future at the drawing board |
title_fullStr | Eliminating oncogenic RAS: back to the future at the drawing board |
title_full_unstemmed | Eliminating oncogenic RAS: back to the future at the drawing board |
title_short | Eliminating oncogenic RAS: back to the future at the drawing board |
title_sort | eliminating oncogenic ras: back to the future at the drawing board |
topic | Review Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9987992/ https://www.ncbi.nlm.nih.gov/pubmed/36688434 http://dx.doi.org/10.1042/BST20221343 |
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