2. Academic Validation
  3. Discovery of novel small molecules targeting TGF-β signaling for the treatment of non-small cell lung cancer

Discovery of novel small molecules targeting TGF-β signaling for the treatment of non-small cell lung cancer

  • Eur J Med Chem. 2025 May 5:289:117442. doi: 10.1016/j.ejmech.2025.117442.
Jie Zhang 1,  Yichen Yin 2,  Baozhen Wang 2,  Jing Chen 3,  Huaiyu Yang 4,  Tao Li 5,  Yihua Chen 6
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
  • 2 School of Clinical Medicine, Ningxia Medical University, Ningxia, 750004, China; Key Laboratory of Fertility Maintenance Ministry of Education, Ningxia Medical University, Ningxia, 750004, China.
  • 3 School of Basic Medical Sciences, Ningxia Medical University, Ningxia, 750004, China; Key Laboratory of Fertility Maintenance Ministry of Education, Ningxia Medical University, Ningxia, 750004, China.
  • 4 Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: hyyang@bio.ecnu.edu.cn.
  • 5 Department of Surgical Oncology, Tumor Hospital, The General Hospital of Ningxia Medical University, Ningxia, China. Electronic address: lit1979@163.com.
  • 6 School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products and Yunnan College of Modern Biomedical Industry, Kunming Medical University, Kunming, Yunnan, 650500, China. Electronic address: chenyihua@kmmu.edu.cn.
PMID: 40081103 DOI: 10.1016/j.ejmech.2025.117442
Abstract

Acquired resistance to tyrosine kinase inhibitors (TKIs) has become a significant challenge in Cancer therapy, underscoring the urgent need for developing alternative therapeutic targets to relieve it. Targeting TGF-β signaling pathway has been emerging as a promising antitumor strategy due to its pivotal role in Cancer progression and metastasis. Our previous study identified YR-290 as an Anticancer molecule through inhibiting TGF-β signaling, but its poor solubility limited its subsequent development. To addressed the limitations, a new series of YR-290 analogues containing hydrophilic moieties were synthesized and evaluated to improve solubility and potency. The optimal compound 8dc, whose solubility also promoted over 4.7-fold compared to YR-290, showed significant inhibition with IC50 values of 0.05 and 0.09 μM in A549 and NCI-H441, respectively. In addition, 8dc remarkably exhibited anti-NSCLC activities in colony formation, migration and invasion with a concentration-dependent manner in vitro. It also affected cell cycle and induced cell Apoptosis in A549 cells. More importantly, 8dc suppressed tumor growth in vivo with minimum toxicity. Mechanism study showed that 8dc exerted Anticancer bioactivity by inhibition against TGF-β signaling.

Keywords

Anticancer; TGF-β; Tetrahydro-β-carboline; Water solubility.

Figures
Products