Cargando…
Targeting Ras with protein engineering
Ras proteins are small GTPases that regulate cell growth and division. Mutations in Ras genes are associated with many types of cancer, making them attractive targets for cancer therapy. Despite extensive efforts, targeting Ras proteins with small molecules has been extremely challenging due to Ras’...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10317039/ https://www.ncbi.nlm.nih.gov/pubmed/37395750 http://dx.doi.org/10.18632/oncotarget.28469 |
_version_ | 1785067830385836032 |
---|---|
author | Tomazini, Atilio Shifman, Julia M. |
author_facet | Tomazini, Atilio Shifman, Julia M. |
author_sort | Tomazini, Atilio |
collection | PubMed |
description | Ras proteins are small GTPases that regulate cell growth and division. Mutations in Ras genes are associated with many types of cancer, making them attractive targets for cancer therapy. Despite extensive efforts, targeting Ras proteins with small molecules has been extremely challenging due to Ras’s mostly flat surface and lack of small molecule-binding cavities. These challenges were recently overcome by the development of the first covalent small-molecule anti-Ras drug, sotorasib, highlighting the efficacy of Ras inhibition as a therapeutic strategy. However, this drug exclusively inhibits the Ras G12C mutant, which is not a prevalent mutation in most cancer types. Unlike the G12C variant, other Ras oncogenic mutants lack reactive cysteines, rendering them unsuitable for targeting via the same strategy. Protein engineering has emerged as a promising method to target Ras, as engineered proteins have the ability to recognize various surfaces with high affinity and specificity. Over the past few years, scientists have engineered antibodies, natural Ras effectors, and novel binding domains to bind to Ras and counteract its carcinogenic activities via a variety of strategies. These include inhibiting Ras-effector interactions, disrupting Ras dimerization, interrupting Ras nucleotide exchange, stimulating Ras interaction with tumor suppressor genes, and promoting Ras degradation. In parallel, significant advancements have been made in intracellular protein delivery, enabling the delivery of the engineered anti-Ras agents into the cellular cytoplasm. These advances offer a promising path for targeting Ras proteins and other challenging drug targets, opening up new opportunities for drug discovery and development. |
format | Online Article Text |
id | pubmed-10317039 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-103170392023-07-04 Targeting Ras with protein engineering Tomazini, Atilio Shifman, Julia M. Oncotarget Review Ras proteins are small GTPases that regulate cell growth and division. Mutations in Ras genes are associated with many types of cancer, making them attractive targets for cancer therapy. Despite extensive efforts, targeting Ras proteins with small molecules has been extremely challenging due to Ras’s mostly flat surface and lack of small molecule-binding cavities. These challenges were recently overcome by the development of the first covalent small-molecule anti-Ras drug, sotorasib, highlighting the efficacy of Ras inhibition as a therapeutic strategy. However, this drug exclusively inhibits the Ras G12C mutant, which is not a prevalent mutation in most cancer types. Unlike the G12C variant, other Ras oncogenic mutants lack reactive cysteines, rendering them unsuitable for targeting via the same strategy. Protein engineering has emerged as a promising method to target Ras, as engineered proteins have the ability to recognize various surfaces with high affinity and specificity. Over the past few years, scientists have engineered antibodies, natural Ras effectors, and novel binding domains to bind to Ras and counteract its carcinogenic activities via a variety of strategies. These include inhibiting Ras-effector interactions, disrupting Ras dimerization, interrupting Ras nucleotide exchange, stimulating Ras interaction with tumor suppressor genes, and promoting Ras degradation. In parallel, significant advancements have been made in intracellular protein delivery, enabling the delivery of the engineered anti-Ras agents into the cellular cytoplasm. These advances offer a promising path for targeting Ras proteins and other challenging drug targets, opening up new opportunities for drug discovery and development. Impact Journals LLC 2023-07-01 /pmc/articles/PMC10317039/ /pubmed/37395750 http://dx.doi.org/10.18632/oncotarget.28469 Text en Copyright: © 2023 Tomazini and Shifman. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Review Tomazini, Atilio Shifman, Julia M. Targeting Ras with protein engineering |
title | Targeting Ras with protein engineering |
title_full | Targeting Ras with protein engineering |
title_fullStr | Targeting Ras with protein engineering |
title_full_unstemmed | Targeting Ras with protein engineering |
title_short | Targeting Ras with protein engineering |
title_sort | targeting ras with protein engineering |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10317039/ https://www.ncbi.nlm.nih.gov/pubmed/37395750 http://dx.doi.org/10.18632/oncotarget.28469 |
work_keys_str_mv | AT tomaziniatilio targetingraswithproteinengineering AT shifmanjuliam targetingraswithproteinengineering |