A Novel CSN5 Inhibitor Drives Tumor-Intrinsic PD-L1 Degradation and Exerts Direct Antitumor Efficacy in Triple-Negative Breast Cancer

  • J Med Chem. 2026 Mar 12;69(5):5540-5559. doi: 10.1021/acs.jmedchem.5c02669.
Yanjun Wang  1 ,  Hui Lei  1  2 ,  Wenyi Liu  1  2 ,  Xindie Li  1 ,  Siyi Jiang  1 ,  Hang Zhang  1 ,  Rui Xiong  1 ,  Zhiwen Yang  1 ,  Yu-Hang Yan  3 ,  Yingying Jiang  1 ,  Ming Lei  4 ,  Guo-Bo Li  3 ,  Hua-Li Wang  2 ,  Lingling Yang  1
Affiliations
  • 1. Sichuan Provincial Engineering Research Center of Molecular Targeted Diagnostic and Therapeutic Drugs, College of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China.
  • 2. Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, Guangdong 518053, China.
  • 3. Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 4. Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, U.K.
PMID: 41705680 DOI: 10.1021/acs.jmedchem.5c02669
Abstract

Targeting the oncoprotein CSN5 represents a promising therapeutic strategy for triple-negative breast Cancer (TNBC), given its critical role in stabilizing PD-L1 and promoting tumor progression. Here, we developed a novel series of 4-NH-substituted azaindole derivatives as potent CSN5 inhibitors. Among them, through systematic structural modifications and SAR analysis at key positions, we identified 30 as a potent candidate with an IC50 of 0.58 μM. This compound effectively inhibited CSN5 activity, promoted NEDD8-Cul1 accumulation, and triggered tumor cell-autonomous PD-L1 degradation. It exhibited multimodal antitumor mechanisms in TNBC models, including P21/P27-mediated G0/G1 arrest, DNA damage induction, and P53/Bax-dependent Apoptosis with Bcl-2 downregulation. In MDA-MB-231 xenografts, compound 30 significantly inhibited tumor growth in a dose-dependent manner without observable toxicity. These findings highlight compound 30 as a promising therapeutic candidate for TNBC treatment through CSN5 inhibition, which simultaneously induces PD-L1 degradation and direct antitumor activity.

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