2. Academic Validation
  3. Network Medicine-Based Strategy Identifies Maprotiline as a Repurposable Drug by Inhibiting PD-L1 Expression via Targeting SPOP in Cancer

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

  • Adv Sci (Weinh). 2025 Jan;12(1):e2410285. doi: 10.1002/advs.202410285.
Saisai Tian 1,  Mengting Xu 2,  Xiangxin Geng 2,  Jiansong Fang 3,  Hanchen Xu 4,  Xinying Xue 5,  Hongmei Hu 2,  Qing Zhang 2,  Dianping Yu 2,  Mengmeng Guo 2,  Hongwei Zhang 2,  Jinyuan Lu 1,  Chengyang Guo 1,  Qun Wang 2,  Sanhong Liu 2,  Weidong Zhang 1 6 7
Affiliations

Affiliations

  • 1 Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai, 200433, China.
  • 2 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
  • 3 Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
  • 4 Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
  • 5 Department of Respiratory and Critical Care, Emergency and Critical Care Medical Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
  • 6 State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China.
  • 7 The Research Center for Traditional Chinese Medicine, Shanghai Institute of Infectious Diseases and Biosafety, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
PMID: 39499771 DOI: 10.1002/advs.202410285
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.

Keywords

Mnet‐DRI; PD‐L1; colorectal cancer; immune checkpoint inhibitors; lung cancer; maprotiline.

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