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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...

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Autores principales: Steffen, Candy Laura, Kaya, Pelin, Schaffner-Reckinger, Elisabeth, Abankwa, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Portland Press Ltd. 2023
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.
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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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