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Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)
Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors h...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Taylor & Francis
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470090/ https://www.ncbi.nlm.nih.gov/pubmed/32779949 http://dx.doi.org/10.1080/14756366.2020.1804382 |
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author | Zhang, Zhimin Chang, Xinyue Zhang, Chixiao Zeng, Shenxin Liang, Meihao Ma, Zhen Wang, Zunyuan Huang, Wenhai Shen, Zhengrong |
author_facet | Zhang, Zhimin Chang, Xinyue Zhang, Chixiao Zeng, Shenxin Liang, Meihao Ma, Zhen Wang, Zunyuan Huang, Wenhai Shen, Zhengrong |
author_sort | Zhang, Zhimin |
collection | PubMed |
description | Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown. |
format | Online Article Text |
id | pubmed-7470090 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
spelling | pubmed-74700902020-09-15 Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1) Zhang, Zhimin Chang, Xinyue Zhang, Chixiao Zeng, Shenxin Liang, Meihao Ma, Zhen Wang, Zunyuan Huang, Wenhai Shen, Zhengrong J Enzyme Inhib Med Chem Research Paper Poly(ADP-ribose) polymerase-1 (PARP-1), a critical DNA repair enzyme in the base excision repair pathway, has been pursued as an attractive cancer therapeutic target. Intervention with PARP-1 has been proved to be more sensitive to cancer cells carrying BRCA1/2 mutations. Several PARP-1 inhibitors have been available on market for the treatment of breast, ovarian and prostatic cancer. Promisingly, the newly developed proteolysis targeting chimaeras (PROTACs) may provide a more potential strategy based on the degradation of PARP-1. Here we report the design, synthesis, and evaluation of a proteolysis targeting chimaera (PROTAC) based on the combination of PARP-1 inhibitor olaparib and the CRBN (cereblon) ligand lenalidomide. In SW620 cells, our probe-quality degrader compound 2 effectively induced PARP-1 degradation which results in anti-proliferation, cells apoptosis, cell cycle arresting, and cancer cells migratory inhibition. Thus, our findings qualify a new chemical probe for PARP-1 knockdown. Taylor & Francis 2020-08-11 /pmc/articles/PMC7470090/ /pubmed/32779949 http://dx.doi.org/10.1080/14756366.2020.1804382 Text en © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (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 | Research Paper Zhang, Zhimin Chang, Xinyue Zhang, Chixiao Zeng, Shenxin Liang, Meihao Ma, Zhen Wang, Zunyuan Huang, Wenhai Shen, Zhengrong Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1) |
title | Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1) |
title_full | Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1) |
title_fullStr | Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1) |
title_full_unstemmed | Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1) |
title_short | Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1) |
title_sort | identification of probe-quality degraders for poly(adp-ribose) polymerase-1 (parp-1) |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470090/ https://www.ncbi.nlm.nih.gov/pubmed/32779949 http://dx.doi.org/10.1080/14756366.2020.1804382 |
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