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Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases
The success of small molecule therapeutics that promotes degradation of critical cancer targets has fueled an intense effort to mimic this activity with bispecific molecules called PROTACs (proteolysis targeting chimeras). The simultaneous binding of PROTACs to a ligase and target can induce proximi...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919295/ https://www.ncbi.nlm.nih.gov/pubmed/35295813 http://dx.doi.org/10.1016/j.isci.2022.103985 |
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author | Luo, Xin Archibeque, Ivonne Dellamaggiore, Ken Smither, Kate Homann, Oliver Lipford, James Russell Mohl, Dane |
author_facet | Luo, Xin Archibeque, Ivonne Dellamaggiore, Ken Smither, Kate Homann, Oliver Lipford, James Russell Mohl, Dane |
author_sort | Luo, Xin |
collection | PubMed |
description | The success of small molecule therapeutics that promotes degradation of critical cancer targets has fueled an intense effort to mimic this activity with bispecific molecules called PROTACs (proteolysis targeting chimeras). The simultaneous binding of PROTACs to a ligase and target can induce proximity-driven ubiquitination and degradation. VHL and CRBN are the two best characterized PROTAC ligases, but the rules governing their cellular activities remain unclear. To establish these requirements and extend them to new ligases, we screened a panel of 56 cell lines with two potent PROTACs that utilized VHL, MZ1, or CRBN, dBET1 to induce degradation of BRD4. With notable exceptions, MZ1 was broadly active in the panel whereas dBET1 was frequently inactive. A search for predictive biomarkers of PROTAC activity found that expression and mutation of VHL and CRBN were themselves predictors of PROTAC activity in the cell line panel. |
format | Online Article Text |
id | pubmed-8919295 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-89192952022-03-15 Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases Luo, Xin Archibeque, Ivonne Dellamaggiore, Ken Smither, Kate Homann, Oliver Lipford, James Russell Mohl, Dane iScience Article The success of small molecule therapeutics that promotes degradation of critical cancer targets has fueled an intense effort to mimic this activity with bispecific molecules called PROTACs (proteolysis targeting chimeras). The simultaneous binding of PROTACs to a ligase and target can induce proximity-driven ubiquitination and degradation. VHL and CRBN are the two best characterized PROTAC ligases, but the rules governing their cellular activities remain unclear. To establish these requirements and extend them to new ligases, we screened a panel of 56 cell lines with two potent PROTACs that utilized VHL, MZ1, or CRBN, dBET1 to induce degradation of BRD4. With notable exceptions, MZ1 was broadly active in the panel whereas dBET1 was frequently inactive. A search for predictive biomarkers of PROTAC activity found that expression and mutation of VHL and CRBN were themselves predictors of PROTAC activity in the cell line panel. Elsevier 2022-02-26 /pmc/articles/PMC8919295/ /pubmed/35295813 http://dx.doi.org/10.1016/j.isci.2022.103985 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Article Luo, Xin Archibeque, Ivonne Dellamaggiore, Ken Smither, Kate Homann, Oliver Lipford, James Russell Mohl, Dane Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases |
title | Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases |
title_full | Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases |
title_fullStr | Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases |
title_full_unstemmed | Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases |
title_short | Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases |
title_sort | profiling of diverse tumor types establishes the broad utility of vhl-based protacs and triages candidate ubiquitin ligases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919295/ https://www.ncbi.nlm.nih.gov/pubmed/35295813 http://dx.doi.org/10.1016/j.isci.2022.103985 |
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