Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trialsResearch in context
Summary: Background: Lupus nephritis (LN) is one of the most common and severe complications of systemic lupus erythematosus (SLE). Multitarget therapy (MT) achieves a 20% higher complete remission (CR) rate compared to conventional therapy in LN management. Intrigued by its excellent clinical effi...
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Elsevier
2025-02-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396424005899 |
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| author | Yue Zhao Zuguo Zheng Xuexiao Jin Shaoshan Liang Changming Zhang Mingchao Zhang Yue Lang Ping Li Zhihong Liu |
| author_facet | Yue Zhao Zuguo Zheng Xuexiao Jin Shaoshan Liang Changming Zhang Mingchao Zhang Yue Lang Ping Li Zhihong Liu |
| author_sort | Yue Zhao |
| collection | DOAJ |
| description | Summary: Background: Lupus nephritis (LN) is one of the most common and severe complications of systemic lupus erythematosus (SLE). Multitarget therapy (MT) achieves a 20% higher complete remission (CR) rate compared to conventional therapy in LN management. Intrigued by its excellent clinical efficacy, we aimed to develop a single-agent therapy with comparable efficacy to MT, offering a simplified treatment regimen. Methods: AZD1152, an Aurora kinase B (Aurkb) inhibitor, was identified through transcriptomic analyses and the L1000 CMap drug repurposing database. The therapeutic efficacy of AZD1152 was evaluated in MRL/lpr mice. Transcriptome sequencing and functional assays were performed to elucidate its mechanisms of action. Aurkb expression and its clinical relevance were assessed in lupus-prone mice and patients with LN. Findings: AZD1152 significantly attenuated systemic immune activation and renal injury in MRL/lpr mice, demonstrating efficacy comparable to MT regimens in animal studies. AZD1152 treatment modulated immune-inflammatory pathways in the kidney. Aurkb expression was upregulated in T cells infiltrating the renal interstitium in LN. Additionally, Aurkb expression levels positively correlated with the activity index (AI) and serum creatinine (Scr) in patients with LN. Mechanistic studies revealed that AZD1152 exerts therapeutic effects primarily by inhibiting T-cell proliferation. Interpretation: This study presents a drug development strategy that integrates clinically validated LN therapies with drug repurposing approaches. This strategy could accelerate drug development and clinical translation processes for LN. Funding: A full list of funding sources can be found in the acknowledgements section. |
| format | Article |
| id | doaj-art-6e543261fcf9424f98d4aee71a654db8 |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-6e543261fcf9424f98d4aee71a654db82025-01-12T05:25:17ZengElsevierEBioMedicine2352-39642025-02-01112105553Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trialsResearch in contextYue Zhao0Zuguo Zheng1Xuexiao Jin2Shaoshan Liang3Changming Zhang4Mingchao Zhang5Yue Lang6Ping Li7Zhihong Liu8National Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, ChinaInstitute of Immunology and Department of Rheumatology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310058, PR ChinaNational Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, ChinaNational Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, ChinaNational Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, ChinaNational Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, ChinaState Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, ChinaNational Clinical Research Center of Kidney Diseases, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 210002, China; Corresponding author.Summary: Background: Lupus nephritis (LN) is one of the most common and severe complications of systemic lupus erythematosus (SLE). Multitarget therapy (MT) achieves a 20% higher complete remission (CR) rate compared to conventional therapy in LN management. Intrigued by its excellent clinical efficacy, we aimed to develop a single-agent therapy with comparable efficacy to MT, offering a simplified treatment regimen. Methods: AZD1152, an Aurora kinase B (Aurkb) inhibitor, was identified through transcriptomic analyses and the L1000 CMap drug repurposing database. The therapeutic efficacy of AZD1152 was evaluated in MRL/lpr mice. Transcriptome sequencing and functional assays were performed to elucidate its mechanisms of action. Aurkb expression and its clinical relevance were assessed in lupus-prone mice and patients with LN. Findings: AZD1152 significantly attenuated systemic immune activation and renal injury in MRL/lpr mice, demonstrating efficacy comparable to MT regimens in animal studies. AZD1152 treatment modulated immune-inflammatory pathways in the kidney. Aurkb expression was upregulated in T cells infiltrating the renal interstitium in LN. Additionally, Aurkb expression levels positively correlated with the activity index (AI) and serum creatinine (Scr) in patients with LN. Mechanistic studies revealed that AZD1152 exerts therapeutic effects primarily by inhibiting T-cell proliferation. Interpretation: This study presents a drug development strategy that integrates clinically validated LN therapies with drug repurposing approaches. This strategy could accelerate drug development and clinical translation processes for LN. Funding: A full list of funding sources can be found in the acknowledgements section.http://www.sciencedirect.com/science/article/pii/S2352396424005899Lupus nephritis (LN)Drug repurposingAZD1152Aurkb |
| spellingShingle | Yue Zhao Zuguo Zheng Xuexiao Jin Shaoshan Liang Changming Zhang Mingchao Zhang Yue Lang Ping Li Zhihong Liu Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trialsResearch in context EBioMedicine Lupus nephritis (LN) Drug repurposing AZD1152 Aurkb |
| title | Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trialsResearch in context |
| title_full | Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trialsResearch in context |
| title_fullStr | Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trialsResearch in context |
| title_full_unstemmed | Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trialsResearch in context |
| title_short | Aurora kinase B inhibitor AZD1152: repurposing for treatment of lupus nephritis driven by the results of clinical trialsResearch in context |
| title_sort | aurora kinase b inhibitor azd1152 repurposing for treatment of lupus nephritis driven by the results of clinical trialsresearch in context |
| topic | Lupus nephritis (LN) Drug repurposing AZD1152 Aurkb |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424005899 |
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