Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent
Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplemen...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2024-02-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383523004276 |
| _version_ | 1797341194884218880 |
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| author | Xin Chen Xianggang Mu Lele Ding Xi Wang Fei Mao Jinlian Wei Qian Liu Yixiang Xu Shuaishuai Ni Lijun Jia Jian Li |
| author_facet | Xin Chen Xianggang Mu Lele Ding Xi Wang Fei Mao Jinlian Wei Qian Liu Yixiang Xu Shuaishuai Ni Lijun Jia Jian Li |
| author_sort | Xin Chen |
| collection | DOAJ |
| description | Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel “trilogy of drug repurposing” strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the “trilogy of drug repurposing” strategy in the development of bi-functional co-therapy agents. |
| first_indexed | 2024-03-08T10:15:27Z |
| format | Article |
| id | doaj.art-31ed866546fd40fdadb95d793268239c |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-03-08T10:15:27Z |
| publishDate | 2024-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-31ed866546fd40fdadb95d793268239c2024-01-29T04:15:23ZengElsevierActa Pharmaceutica Sinica B2211-38352024-02-01142729750Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agentXin Chen0Xianggang Mu1Lele Ding2Xi Wang3Fei Mao4Jinlian Wei5Qian Liu6Yixiang Xu7Shuaishuai Ni8Lijun Jia9Jian Li10State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; College of Pharmacy, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, ChinaState Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, ChinaCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Corresponding authors.Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China; Corresponding authors.State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Corresponding authors.Chemotherapy-induced complications, particularly lethal cardiovascular diseases, pose significant challenges for cancer survivors. The intertwined adverse effects, brought by cancer and its complication, further complicate anticancer therapy and lead to diminished clinical outcomes. Simple supplementation of cardioprotective agents falls short in addressing these challenges. Developing bi-functional co-therapy agents provided another potential solution to consolidate the chemotherapy and reduce cardiac events simultaneously. Drug repurposing was naturally endowed with co-therapeutic potential of two indications, implying a unique chance in the development of bi-functional agents. Herein, we further proposed a novel “trilogy of drug repurposing” strategy that comprises function-based, target-focused, and scaffold-driven repurposing approaches, aiming to systematically elucidate the advantages of repurposed drugs in rationally developing bi-functional agent. Through function-based repurposing, a cardioprotective agent, carvedilol (CAR), was identified as a potential neddylation inhibitor to suppress lung cancer growth. Employing target-focused SAR studies and scaffold-driven drug design, we synthesized 44 CAR derivatives to achieve a balance between anticancer and cardioprotection. Remarkably, optimal derivative 43 displayed promising bi-functional effects, especially in various self-established heart failure mice models with and without tumor-bearing. Collectively, the present study validated the practicability of the “trilogy of drug repurposing” strategy in the development of bi-functional co-therapy agents.http://www.sciencedirect.com/science/article/pii/S2211383523004276AnticancerHeart failureComplicationDrug repurposingBi-functional drug |
| spellingShingle | Xin Chen Xianggang Mu Lele Ding Xi Wang Fei Mao Jinlian Wei Qian Liu Yixiang Xu Shuaishuai Ni Lijun Jia Jian Li Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent Acta Pharmaceutica Sinica B Anticancer Heart failure Complication Drug repurposing Bi-functional drug |
| title | Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent |
| title_full | Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent |
| title_fullStr | Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent |
| title_full_unstemmed | Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent |
| title_short | Trilogy of drug repurposing for developing cancer and chemotherapy-induced heart failure co-therapy agent |
| title_sort | trilogy of drug repurposing for developing cancer and chemotherapy induced heart failure co therapy agent |
| topic | Anticancer Heart failure Complication Drug repurposing Bi-functional drug |
| url | http://www.sciencedirect.com/science/article/pii/S2211383523004276 |
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