2. Academic Validation
  3. Discovery of potent and selective STAT3 inhibitors against triple-negative breast cancer

Discovery of potent and selective STAT3 inhibitors against triple-negative breast cancer

  • Eur J Med Chem. 2025 Nov 15:298:118020. doi: 10.1016/j.ejmech.2025.118020.
Ru Wang 1,  Liang-Peng Li 1,  Chen Zhao 1,  Ya-Dong Yang 1,  Xin Li 1,  Bei-Bei Yang 1,  Ting-Ting Du 2,  Peng Song 3,  Li Li 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 2 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: ninadu@imm.ac.cn.
  • 3 Department of Medical Oncology, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing, 100853, China. Electronic address: b2005098@sina.com.
  • 4 State Key Laboratory of Digestive Health, Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China. Electronic address: annaleelin@imm.ac.cn.
PMID: 40774067 DOI: 10.1016/j.ejmech.2025.118020
Abstract

The development of effective targeted therapies for triple-negative breast Cancer (TNBC) remains challenging due to its diverse molecular subtypes and intrinsically aggressive tumor biology. Constitutive STAT3 activation drives TNBC pathogenesis and confers treatment resistance, establishing it as a promising precision oncology target. In this study, LZJ66 (previously designated as compound 40) was used as the lead compound for further optimization. Among the 42 designed compounds, W36 emerged as a high binding affinity inhibitor of STAT3 (KD = 323.3 nM), demonstrating dual suppression of STAT3 phosphorylation and proliferation in the STAT3-overactivated TNBC cell lines MDA-MB-231 (IC50 = 0.61 ± 0.31 μM) and MDA-MB-468 (IC50 = 0.65 ± 0.12 μM). Its antitumor efficacy has extended to Other TNBC cell lines, with dose-dependent suppression of TNBC growth in xenograft model, supporting its potential for clinical translation.

Keywords

Benzimidazole derivatives; STAT3; Structure optimization; TNBC.

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