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Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras
Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective th...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9750146/ https://www.ncbi.nlm.nih.gov/pubmed/36516252 http://dx.doi.org/10.1126/sciadv.abq2216 |
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author | Do, Thang Cong Lau, Jun Wei Sun, Caixia Liu, Songhan Kha, Khoa Tuan Lim, Seok Ting Oon, Yu Yang Kwan, Yuet Ping Ma, Jia Jia Mu, Yuguang Liu, Xiaogang Carney, Thomas James Wang, Xiaomeng Xing, Bengang |
author_facet | Do, Thang Cong Lau, Jun Wei Sun, Caixia Liu, Songhan Kha, Khoa Tuan Lim, Seok Ting Oon, Yu Yang Kwan, Yuet Ping Ma, Jia Jia Mu, Yuguang Liu, Xiaogang Carney, Thomas James Wang, Xiaomeng Xing, Bengang |
author_sort | Do, Thang Cong |
collection | PubMed |
description | Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment-activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future. |
format | Online Article Text |
id | pubmed-9750146 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-97501462022-12-21 Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras Do, Thang Cong Lau, Jun Wei Sun, Caixia Liu, Songhan Kha, Khoa Tuan Lim, Seok Ting Oon, Yu Yang Kwan, Yuet Ping Ma, Jia Jia Mu, Yuguang Liu, Xiaogang Carney, Thomas James Wang, Xiaomeng Xing, Bengang Sci Adv Biomedicine and Life Sciences Epigenetic mediation through bromodomain and extraterminal (BET) proteins have progressively translated protein imbalance into effective cancer treatment. Perturbation of druggable BET proteins through proteolysis-targeting chimeras (PROTACs) has recently contributed to the discovery of effective therapeutics. Unfortunately, precise and microenvironment-activatable BET protein degradation content with promising tumor selectivity and pharmacological suitability remains elusive. Here, we present an enzyme-derived clicking PROTACs (ENCTACs) capable of orthogonally cross-linking two disparate small-molecule warhead ligands that recognize BET bromodomain-containing protein 4 (BRD4) protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme. This localized formation of heterobifunctional degraders promotes specific down-regulation of BRD4, which subsequently alters expression of epigenetic targets and, therefore, allows precise modulation of hypoxic signaling in live cells, zebrafish, and living mice with solid tumors. Our activation-feedback system demonstrates compelling superiorities and may enable the PROTAC technology with more flexible practicality and druggable potency for precision medicine in the near future. American Association for the Advancement of Science 2022-12-14 /pmc/articles/PMC9750146/ /pubmed/36516252 http://dx.doi.org/10.1126/sciadv.abq2216 Text en Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Biomedicine and Life Sciences Do, Thang Cong Lau, Jun Wei Sun, Caixia Liu, Songhan Kha, Khoa Tuan Lim, Seok Ting Oon, Yu Yang Kwan, Yuet Ping Ma, Jia Jia Mu, Yuguang Liu, Xiaogang Carney, Thomas James Wang, Xiaomeng Xing, Bengang Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
title | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
title_full | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
title_fullStr | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
title_full_unstemmed | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
title_short | Hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
title_sort | hypoxia deactivates epigenetic feedbacks via enzyme-derived clicking proteolysis-targeting chimeras |
topic | Biomedicine and Life Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9750146/ https://www.ncbi.nlm.nih.gov/pubmed/36516252 http://dx.doi.org/10.1126/sciadv.abq2216 |
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