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...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2020-01-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/14756366.2020.1804382 |
| _version_ | 1818972898374713344 |
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| author | Zhimin Zhang Xinyue Chang Chixiao Zhang Shenxin Zeng Meihao Liang Zhen Ma Zunyuan Wang Wenhai Huang Zhengrong Shen |
| author_facet | Zhimin Zhang Xinyue Chang Chixiao Zhang Shenxin Zeng Meihao Liang Zhen Ma Zunyuan Wang Wenhai Huang Zhengrong Shen |
| author_sort | Zhimin Zhang |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-20T15:15:35Z |
| format | Article |
| id | doaj.art-7a93c6b4612e48189e7b560a91de485e |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-12-20T15:15:35Z |
| publishDate | 2020-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-7a93c6b4612e48189e7b560a91de485e2022-12-21T19:36:11ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742020-01-013511606161510.1080/14756366.2020.18043821804382Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1)Zhimin Zhang0Xinyue Chang1Chixiao Zhang2Shenxin Zeng3Meihao Liang4Zhen Ma5Zunyuan Wang6Wenhai Huang7Zhengrong Shen8Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegeKey Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegeKey Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegeKey Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegeKey Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegeKey Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegeKey Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegeKey Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegeKey Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical CollegePoly(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.http://dx.doi.org/10.1080/14756366.2020.1804382parp-1protactarget protein knockdown |
| spellingShingle | Zhimin Zhang Xinyue Chang Chixiao Zhang Shenxin Zeng Meihao Liang Zhen Ma Zunyuan Wang Wenhai Huang Zhengrong Shen Identification of probe-quality degraders for Poly(ADP-ribose) polymerase-1 (PARP-1) Journal of Enzyme Inhibition and Medicinal Chemistry parp-1 protac target protein knockdown |
| 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 | parp-1 protac target protein knockdown |
| url | http://dx.doi.org/10.1080/14756366.2020.1804382 |
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