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Updated: Jun 26, 2025

Isolation and Characterization of Neutrophils with Anti-Tumor Properties
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Isolation and Characterization of Neutrophils with Anti-Tumor Properties

Published on: June 19, 2015

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A β-Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment

Di Zhu1,2, Yu Lu1,2, Zhanchao Yan3

  • 1Department of Medicinal Chemistry, College of Pharmaceutical Sciences of Capital Medical University, Beijing 100069, P. R. China.

Journal of Medicinal Chemistry
|May 10, 2024
PubMed

Insights

A novel peptidyl arginine deiminase 4 (PAD4) inhibitor, compound 28, effectively targets triple-negative breast cancer (TNBC) by inhibiting tumor growth and metastasis. This compound also enhances the anti-tumor immune response, offering a dual therapeutic strategy.

Area of Science:

  • Medicinal Chemistry
  • Cancer Biology
  • Immunology

Background:

  • Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and high recurrence rates.
  • Histone citrullination-mediated chromatin dysregulation is a key factor in TNBC progression.
  • Targeting epigenetic alterations offers a promising therapeutic avenue for TNBC.

Purpose of the Study:

  • To synthesize and evaluate novel beta-carboline-derived peptidyl arginine deiminase 4 (PAD4) inhibitors for TNBC therapy.
  • To identify a potent PAD4 inhibitor with anti-tumor and immunomodulatory effects.
  • To investigate the therapeutic potential of compound 28 in preclinical TNBC models.

Main Methods:

  • Synthesis and optimization of beta-carboline derivatives as PAD4 inhibitors.
  • In vitro evaluation of TNBC cell proliferation inhibition.
  • In vivo assessment of compound 28 in the 4T1 in situ mouse model for solid tumor and metastasis inhibition.
  • Analysis of the tumor immune microenvironment modulation by compound 28.

Main Results:

  • A novel series of beta-carboline-derived PAD4 inhibitors were synthesized, with compound 28 showing potent TNBC cell proliferation inhibition.
  • Compound 28 effectively hindered the PAD4-H3cit-NET signaling pathway.
  • In vivo studies demonstrated that compound 28 inhibited solid tumor growth and pulmonary metastatic nodules in the 4T1 mouse model.
  • Compound 28 significantly improved the tumor immune microenvironment by modulating immune cell populations.

Conclusions:

  • Compound 28 is a highly effective PAD4 inhibitor with significant anti-tumor and anti-metastatic activity against TNBC.
  • Compound 28 demonstrates a dual therapeutic mechanism, combining conventional anti-cancer effects with immune-boosting properties.
  • Compound 28 represents a promising novel therapeutic strategy for treating triple-negative breast cancer.

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