2. Academic Validation
  3. Chemical Space Navigation of Nitidine Leads to the Discovery of a Novel PD-L1 Degradation Agent by Targeting CSN5 for Enhanced Antitumor Immunity

Chemical Space Navigation of Nitidine Leads to the Discovery of a Novel PD-L1 Degradation Agent by Targeting CSN5 for Enhanced Antitumor Immunity

  • J Med Chem. 2026 Apr 9;69(7):8237-8254. doi: 10.1021/acs.jmedchem.5c03636.
Qun Wang 1,  Mengmeng Guo 1,  Yujia Song 2,  Kai Cui 3,  Hongmei Hu 1,  Xinying Xue 4,  Dianping Yu 1,  Hanchen Xu 5,  Qing Zhang 1,  Mengting Xu 1,  Hanchi Xu 1,  Linyang Li 1,  Shize Xie 2,  Mei Xie 4,  Shuzhen Lyu 6,  Yutong Xie 7,  Sanhong Liu 1,  Weidong Zhang 2 3 8,  Jinxin Wang 2
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 3 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 4 Department of Respiratory and Critical Care, Emergency and Critical Care Medical Center, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
  • 5 Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China.
  • 6 Department of Breast Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
  • 7 Department of Pathology, Chinese PLA General Hospital, The First Medical Centre, Beijing 100141, China.
  • 8 Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.
PMID: 41824767 DOI: 10.1021/acs.jmedchem.5c03636
Abstract

Expanding the chemical space of natural products is an effective strategy for discovering new drug candidates and has achieved remarkable results in activity screening. To efficiently explore the chemical space of nitidine, we developed a one-pot method to synthesize functionalized phenanthridines using commercially available or easily prepared aldehydes. Assisted by pyrrolidine and photocatalysts, the reaction proceeded under visible light at room temperature with satisfactory yields. Activity screening identified derivative e24, which reduced tumor cell PD-L1 expression more effectively than positive control JQ-1, while the prototype nitidine had minimal effects. Critically, e24 specifically targets CSN5, an essential regulatory factor, to induce PD-L1 degradation, thereby blocking the PD-1/PD-L1 interaction between T cells and tumor cells and activating the tumor immune microenvironment. In Lewis tumor and MC38 mice models, e24 exerted antitumor effects by enhancing tumor-infiltrating T-cell immunity and inhibiting the activation of immunosuppressive MDSCs and Tregs.

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