2. Academic Validation
  3. Discovery of Dual PD-L1/HDAC3 Inhibitors for Tumor Immunotherapy

Discovery of Dual PD-L1/HDAC3 Inhibitors for Tumor Immunotherapy

  • J Med Chem. 2025 Apr 24;68(8):8046-8064. doi: 10.1021/acs.jmedchem.4c02529.
Zhijie Wang 1 2,  HaiQi He 2,  Xiaotong Liao 2,  Lin Yuan 2,  Shuding Sun 3,  Chenglong Xu 2,  Xixiang Yang 2,  Qinru Zang 2,  Xiaopeng Peng 4,  Jianjun Chen 2,  Xia Guo 1
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Viral Oncology, Ministry of Science and Innovation, Shenzhen Hospital, Southern Medical University, Shenzhen 518100, China.
  • 2 School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Screening, Southern Medical University, Guangzhou 510515, China.
  • 3 Academy of Chinese Medicine Sciences, Henan University of Chinese Medicine, Zhengzhou, Henan 450046, China.
  • 4 Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Key Laboratory for Tissue Engineering of Jiangxi Province, School of Pharmacy, Gannan Medical University, Ganzhou 341000, PR China.
PMID: 40230281 DOI: 10.1021/acs.jmedchem.4c02529
Abstract

Targeting programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway has been considered as one of the most promising strategies for tumor immunotherapy. However, single-target PD-1/PD-L1 inhibitors frequently exhibit limited efficacy, highlighting the urgent need for new therapies. Herein, a series of dual PD-L1/HDAC3 inhibitors were developed through a pharmacophore fusion strategy for the first time. Among them, compound PH3 was identified as the most promising dual PD-L1/HDAC3 Inhibitor, with potent PD-1/PD-L1 inhibitory activity (IC50 = 89.4 nM) and selective HDAC3 inhibitory activity (IC50 = 107 nM). Moreover, PH3 exhibited superior in vitro antitumor activities and in vitro immune activation effects. Additionally, PH3 showed potent and dose-dependent antitumor efficacy in the B16-F10 melanoma mouse model without obvious toxicity. Furthermore, PH3 increased the infiltration of CD3+CD8+ and CD3+CD4+ cells in the tumor microenvironment. Collectively, PH3 represented a novel dual PD-L1/HDAC3 Inhibitor deserving further investigation as a tumor immunotherapy agent.

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