Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer
Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectiv...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383522004907 |
| _version_ | 1797843870566842368 |
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| author | Yongxi Liang Delin Min Hulin Fan Kunlin Liu Juchuanli Tu Xueyan He Bingjie Liu Lu Zhou Suling Liu Xun Sun |
| author_facet | Yongxi Liang Delin Min Hulin Fan Kunlin Liu Juchuanli Tu Xueyan He Bingjie Liu Lu Zhou Suling Liu Xun Sun |
| author_sort | Yongxi Liang |
| collection | DOAJ |
| description | Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC. |
| first_indexed | 2024-04-09T17:13:03Z |
| format | Article |
| id | doaj.art-bcab8c808f27476ba2abaeeab4a49504 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-09T17:13:03Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-bcab8c808f27476ba2abaeeab4a495042023-04-20T04:36:24ZengElsevierActa Pharmaceutica Sinica B2211-38352023-04-0113416861698Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancerYongxi Liang0Delin Min1Hulin Fan2Kunlin Liu3Juchuanli Tu4Xueyan He5Bingjie Liu6Lu Zhou7Suling Liu8Xun Sun9School of Pharmacy, Fudan University, Shanghai 201203, ChinaSchool of Pharmacy, Fudan University, Shanghai 201203, ChinaSchool of Pharmacy, Fudan University, Shanghai 201203, ChinaSchool of Pharmacy, Fudan University, Shanghai 201203, ChinaFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, ChinaFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, ChinaFudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, ChinaSchool of Pharmacy, Fudan University, Shanghai 201203, China; Corresponding authors.Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China; Corresponding authors.School of Pharmacy, Fudan University, Shanghai 201203, China; The Institutes of Integrative Medicine of Fudan University, Shanghai 200040, China; Corresponding authors.Triple-negative breast cancer (TNBC) is a nasty disease with extremely high malignancy and poor prognosis. Annexin A3 (ANXA3) is a potential prognosis biomarker, displaying an excellent correlation of ANXA3 overexpression with patients' poor prognosis. Silencing the expression of ANXA3 effectively inhibits the proliferation and metastasis of TNBC, suggesting that ANXA3 can be a promising therapeutic target to treat TNBC. Herein, we report a first-in-class ANXA3-targeted small molecule (R)-SL18, which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells. (R)-SL18 directly bound to ANXA3 and increased its ubiquitination, thereby inducing ANXA3 degradation with moderate family selectivity. Importantly, (R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model. Furthermore, (R)-SL18 could reduce the β-catenin level, and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells. Collectively, our data suggested that targeting degradation of ANXA3 by (R)-SL18 possesses the potential to treat TNBC.http://www.sciencedirect.com/science/article/pii/S2211383522004907Annexin A3 (ANXA3)DegraderTriple-negative breast cancerUbiquitinationPatient-derived xenograft |
| spellingShingle | Yongxi Liang Delin Min Hulin Fan Kunlin Liu Juchuanli Tu Xueyan He Bingjie Liu Lu Zhou Suling Liu Xun Sun Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer Acta Pharmaceutica Sinica B Annexin A3 (ANXA3) Degrader Triple-negative breast cancer Ubiquitination Patient-derived xenograft |
| title | Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer |
| title_full | Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer |
| title_fullStr | Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer |
| title_full_unstemmed | Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer |
| title_short | Discovery of a first-in-class ANXA3 degrader for the treatment of triple-negative breast cancer |
| title_sort | discovery of a first in class anxa3 degrader for the treatment of triple negative breast cancer |
| topic | Annexin A3 (ANXA3) Degrader Triple-negative breast cancer Ubiquitination Patient-derived xenograft |
| url | http://www.sciencedirect.com/science/article/pii/S2211383522004907 |
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