Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer

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.

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Publication Details

Journal
Advanced Science
Published
2024-11-05
DOI
https://doi.org/10.1002/advs.202410285
Citations
10
Primary Topic
Tryptophan and brain disorders
Type
article
Field-Weighted Citation Impact
1.57

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article

Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer

Hongmei Hu, Jiansong Fang, Sai Tian, Mengting Xu et al.
10 citations
Advanced Science
Tryptophan and brain disorders
1.57
article

Network Medicine‐Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD‐L1 Expression via Targeting SPOP in Cancer

Hongmei Hu, Jiansong Fang, Sai Tian, Mengting Xu, Hanchen Xu, Sanhong Liu, Qing Zhang, Dianping Yu, Chuanbin Guo, Jinyuan Lu, Qun Wang, Hongwei Zhang, Weidong Zhang, Xinying Xue, Mengmeng Guo, Xiangxin Geng
article en
10 citations

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.

Advanced ScienceVol. 12(1)
Guangzhou University of Chinese Medicine (CN), Second Military Medical University (CN), Capital Medical University (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Shanghai University of Traditional Chinese Medicine (CN), Longhua Hospital Shanghai University of Traditional Chinese Medicine (CN), Beijing Shijitan Hospital (CN)
National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality, National Key Research and Development Program of China
Good health and well-being
Openalex Percentile: Top 17%
Tryptophan and brain disorders
1.57
DOIOpen Access PDFOpenAlex
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