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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...

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Detalles Bibliográficos
Autores principales: Luo, Xin, Archibeque, Ivonne, Dellamaggiore, Ken, Smither, Kate, Homann, Oliver, Lipford, James Russell, Mohl, Dane
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
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.
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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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