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Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity,
PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617031/ https://www.ncbi.nlm.nih.gov/pubmed/34824248 http://dx.doi.org/10.1038/s41467-021-27210-x |
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author | Lv, Dongwen Pal, Pratik Liu, Xingui Jia, Yannan Thummuri, Dinesh Zhang, Peiyi Hu, Wanyi Pei, Jing Zhang, Qi Zhou, Shuo Khan, Sajid Zhang, Xuan Hua, Nan Yang, Qingping Arango, Sebastian Zhang, Weizhou Nayak, Digant Olsen, Shaun K. Weintraub, Susan T. Hromas, Robert Konopleva, Marina Yuan, Yaxia Zheng, Guangrong Zhou, Daohong |
author_facet | Lv, Dongwen Pal, Pratik Liu, Xingui Jia, Yannan Thummuri, Dinesh Zhang, Peiyi Hu, Wanyi Pei, Jing Zhang, Qi Zhou, Shuo Khan, Sajid Zhang, Xuan Hua, Nan Yang, Qingping Arango, Sebastian Zhang, Weizhou Nayak, Digant Olsen, Shaun K. Weintraub, Susan T. Hromas, Robert Konopleva, Marina Yuan, Yaxia Zheng, Guangrong Zhou, Daohong |
author_sort | Lv, Dongwen |
collection | PubMed |
description | PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRL(VHL))/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs. |
format | Online Article Text |
id | pubmed-8617031 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86170312021-12-10 Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, Lv, Dongwen Pal, Pratik Liu, Xingui Jia, Yannan Thummuri, Dinesh Zhang, Peiyi Hu, Wanyi Pei, Jing Zhang, Qi Zhou, Shuo Khan, Sajid Zhang, Xuan Hua, Nan Yang, Qingping Arango, Sebastian Zhang, Weizhou Nayak, Digant Olsen, Shaun K. Weintraub, Susan T. Hromas, Robert Konopleva, Marina Yuan, Yaxia Zheng, Guangrong Zhou, Daohong Nat Commun Article PROteolysis-TArgeting Chimeras (PROTACs) have emerged as an innovative drug development platform. However, most PROTACs have been generated empirically because many determinants of PROTAC specificity and activity remain elusive. Through computational modelling of the entire NEDD8-VHL Cullin RING E3 ubiquitin ligase (CRL(VHL))/PROTAC/BCL-xL/UbcH5B(E2)-Ub/RBX1 complex, we find that this complex can only ubiquitinate the lysines in a defined band region on BCL-xL. Using this approach to guide our development of a series of ABT263-derived and VHL-recruiting PROTACs, we generate a potent BCL-xL and BCL-2 (BCL-xL/2) dual degrader with significantly improved antitumor activity against BCL-xL/2-dependent leukemia cells. Our results provide experimental evidence that the accessibility of lysines on a target protein plays an important role in determining the selectivity and potency of a PROTAC in inducing protein degradation, which may serve as a conceptual framework to guide the future development of PROTACs. Nature Publishing Group UK 2021-11-25 /pmc/articles/PMC8617031/ /pubmed/34824248 http://dx.doi.org/10.1038/s41467-021-27210-x Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Lv, Dongwen Pal, Pratik Liu, Xingui Jia, Yannan Thummuri, Dinesh Zhang, Peiyi Hu, Wanyi Pei, Jing Zhang, Qi Zhou, Shuo Khan, Sajid Zhang, Xuan Hua, Nan Yang, Qingping Arango, Sebastian Zhang, Weizhou Nayak, Digant Olsen, Shaun K. Weintraub, Susan T. Hromas, Robert Konopleva, Marina Yuan, Yaxia Zheng, Guangrong Zhou, Daohong Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, |
title | Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, |
title_full | Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, |
title_fullStr | Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, |
title_full_unstemmed | Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, |
title_short | Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity, |
title_sort | development of a bcl-xl and bcl-2 dual degrader with improved anti-leukemic activity, |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617031/ https://www.ncbi.nlm.nih.gov/pubmed/34824248 http://dx.doi.org/10.1038/s41467-021-27210-x |
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