Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer
Abstract Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side effects of current ICIs, such as programmed death protein‐1, programmed cell deat...
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| Format: | Article |
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Wiley
2025-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410285 |
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| author | Saisai Tian Mengting Xu Xiangxin Geng Jiansong Fang Hanchen Xu Xinying Xue Hongmei Hu Qing Zhang Dianping Yu Mengmeng Guo Hongwei Zhang Jinyuan Lu Chengyang Guo Qun Wang Sanhong Liu Weidong Zhang |
| author_facet | Saisai Tian Mengting Xu Xiangxin Geng Jiansong Fang Hanchen Xu Xinying Xue Hongmei Hu Qing Zhang Dianping Yu Mengmeng Guo Hongwei Zhang Jinyuan Lu Chengyang Guo Qun Wang Sanhong Liu Weidong Zhang |
| author_sort | Saisai Tian |
| collection | DOAJ |
| description | Abstract Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side effects of current ICIs, such as programmed death protein‐1, programmed cell death‐ligand 1, and cytotoxic T lymphocyte‐associated antigen 4 (CTLA4) antibodies, there is an urgent need to find new drugs with ICP inhibitory effects. In this study, a network‐based computational framework called multi‐network algorithm‐driven drug repositioning targeting ICP (Mnet‐DRI) is developed to accurately repurpose novel ICIs from ≈3000 Food and Drug Administration‐approved or investigational drugs. By applying Mnet‐DRI to PD‐L1, maprotiline (MAP), an antidepressant drug is repurposed, as a potential PD‐L1 modifier for colorectal and lung cancers. Experimental validation revealed that MAP reduced PD‐L1 expression by targeting E3 ubiquitin ligase speckle‐type zinc finger structural protein (SPOP), and the combination of MAP and anti‐CTLA4 in vivo significantly enhanced the antitumor effect, providing a new alternative for the clinical treatment of colorectal and lung cancer. |
| format | Article |
| id | doaj-art-2f69a9473416462688b995e81394e109 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-2f69a9473416462688b995e81394e1092025-01-09T11:44:46ZengWileyAdvanced Science2198-38442025-01-01121n/an/a10.1002/advs.202410285Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in CancerSaisai Tian0Mengting Xu1Xiangxin Geng2Jiansong Fang3Hanchen Xu4Xinying Xue5Hongmei Hu6Qing Zhang7Dianping Yu8Mengmeng Guo9Hongwei Zhang10Jinyuan Lu11Chengyang Guo12Qun Wang13Sanhong Liu14Weidong Zhang15Department of Phytochemistry School of Pharmacy Second Military Medical University Shanghai 200433 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaScience and Technology Innovation Center Guangzhou University of Chinese Medicine Guangzhou 510006 ChinaInstitute of Digestive Diseases Longhua Hospital Shanghai University of Traditional Chinese Medicine Shanghai 200032 ChinaDepartment of Respiratory and Critical Care Emergency and Critical Care Medical Center Beijing Shijitan Hospital Capital Medical University Beijing 100038 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaDepartment of Phytochemistry School of Pharmacy Second Military Medical University Shanghai 200433 ChinaDepartment of Phytochemistry School of Pharmacy Second Military Medical University Shanghai 200433 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaShanghai Frontiers Science Center of TCM Chemical Biology Institute of Interdisciplinary Integrative Medicine Research Shanghai University of Traditional Chinese Medicine Shanghai 201203 ChinaDepartment of Phytochemistry School of Pharmacy Second Military Medical University Shanghai 200433 ChinaAbstract Immune checkpoint inhibitors (ICIs) are drugs that inhibit immune checkpoint (ICP) molecules to restore the antitumor activity of immune cells and eliminate tumor cells. Due to the limitations and certain side effects of current ICIs, such as programmed death protein‐1, programmed cell death‐ligand 1, and cytotoxic T lymphocyte‐associated antigen 4 (CTLA4) antibodies, there is an urgent need to find new drugs with ICP inhibitory effects. In this study, a network‐based computational framework called multi‐network algorithm‐driven drug repositioning targeting ICP (Mnet‐DRI) is developed to accurately repurpose novel ICIs from ≈3000 Food and Drug Administration‐approved or investigational drugs. By applying Mnet‐DRI to PD‐L1, maprotiline (MAP), an antidepressant drug is repurposed, as a potential PD‐L1 modifier for colorectal and lung cancers. Experimental validation revealed that MAP reduced PD‐L1 expression by targeting E3 ubiquitin ligase speckle‐type zinc finger structural protein (SPOP), and the combination of MAP and anti‐CTLA4 in vivo significantly enhanced the antitumor effect, providing a new alternative for the clinical treatment of colorectal and lung cancer.https://doi.org/10.1002/advs.202410285colorectal cancerimmune checkpoint inhibitorslung cancermaprotilineMnet‐DRIPD‐L1 |
| spellingShingle | Saisai Tian Mengting Xu Xiangxin Geng Jiansong Fang Hanchen Xu Xinying Xue Hongmei Hu Qing Zhang Dianping Yu Mengmeng Guo Hongwei Zhang Jinyuan Lu Chengyang Guo Qun Wang Sanhong Liu Weidong Zhang Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer Advanced Science colorectal cancer immune checkpoint inhibitors lung cancer maprotiline Mnet‐DRI PD‐L1 |
| title | Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer |
| title_full | Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer |
| title_fullStr | Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer |
| title_full_unstemmed | Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer |
| title_short | Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer |
| title_sort | network medicine based strategy identifies maprotiline as a repurposable drug by inhibiting pd l1 expression via targeting spop in cancer |
| topic | colorectal cancer immune checkpoint inhibitors lung cancer maprotiline Mnet‐DRI PD‐L1 |
| url | https://doi.org/10.1002/advs.202410285 |
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