2. Academic Validation
  3. A β-Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment against Triple-Negative Breast Cancer

A β-Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment against Triple-Negative Breast Cancer

  • J Med Chem. 2024 May 23;67(10):7973-7994. doi: 10.1021/acs.jmedchem.4c00030.
Di Zhu 1 2,  Yu Lu 1 2,  Zhanchao Yan 3,  Qian Deng 1 2,  Bo Hu 1 2,  Yinsong Wang 4,  Wenjing Wang 5,  Yanming Wang 3,  Yuji Wang 1 2 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, P. R. China.
  • 2 Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, Beijing 100069, P. R. China.
  • 3 The First Affiliated Hospital of Henan University, Center for Clinical Research and Translational Medicine, Laboratory of Epigenetics, Henan University, Kaifeng 475004, P. R. China.
  • 4 The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin 300070, P. R. China.
  • 5 Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, P. R. China.
  • 6 Beijing Laboratory of Oral Health, Capital Medical University, Beijing 100069, P. R. China.
PMID: 38728549 DOI: 10.1021/acs.jmedchem.4c00030
Abstract

Triple-negative breast Cancer is a highly aggressive and heterogeneous breast Cancer subtype characterized by early metastasis, poor prognosis, and high recurrence. Targeting histone citrullination-mediated chromatin dysregulation to induce epigenetic alterations shows great promise in TNBC therapy. We report the synthesis, optimization, and evaluation of a novel series of β-carboline-derived peptidyl arginine deiminase 4 inhibitors that exhibited potent inhibition of TNBC cell proliferation. The most outstanding PAD4 inhibitor, compound 28, hindered the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model. Furthermore, 28 improved the tumor immune microenvironment by reshaping neutrophil phenotype, upregulating the proportions of dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived suppressor cells. In conclusion, our work offered 28 as an efficacious PAD4 inhibitor that exerts a combination of conventional chemotherapy and immune-boosting effects, which represents a potential therapy strategy for TNBC.

Figures
Products