The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions

Wu H 1 , Sun Y 2 , Wong WL 3 , Cui J 4 , Li J 5 , You X 2 Show all authors , Yap LF 3 , Huang Y 1 , Hong W 6 , Yang X 7 , Paterson IC 8 , Wang H 9

Affiliations 

  • 1 School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China
  • 2 Laboratory of Pharmacology/Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
  • 3 Department of Oral and Craniofacial Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala, Lumpur, Malaysia
  • 4 Department of Pharmacy, Shaanxi Provincial Hospital of Tuberculosis Prevention and Treatment, Xi'an, 710100, China
  • 5 Department of Pharmacy, Logistics University of Chinese People's Armed Police Forces, Tianjin, 300309, China
  • 6 School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan, 750021, China; Key Laboratory of Chemical Engineering and Technology, State Ethnic Affairs Commission, North Minzu University, Yinchuan, 750021, China. Electronic address: hongwei@nmu.edu.cn
  • 7 Laboratory of Pharmacology/Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: xinyiyang@imb.cams.cn
  • 8 Department of Oral and Craniofacial Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala, Lumpur, Malaysia. Electronic address: ipaterson@um.edu.my
  • 9 School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China; School of Pharmacy, Minzu University of China, Beijing, 100081, China; Key Laboratory of Ethnomedicine (MINZU University of China), Ministry of Education, Beijing, 100081, China. Electronic address: hao.wang@nxmu.edu.cn
Eur J Med Chem, 2020 Mar 01;189:112042.
PMID: 31958737 DOI: 10.1016/j.ejmech.2020.112042

Abstract

Transforming growth factor-β (TGF-β) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-β signaling pathway is a potential target for therapeutic intervention in the development of many diseases, such as fibrosis and cancer. Most currently available inhibitors of TGF-β signaling function as TGF-β receptor I (TβR-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-β receptor II (TβR-II) to interfere with the protein-protein interactions (PPIs) between TGF-β and its receptors. One compound, CJJ300, inhibited TGF-β signaling by disrupting the formation of the TGF-β-TβR-I-TβR-II signaling complex. Treatment of A549 cells with CJJ300 resulted in the inhibition of downstream signaling events such as the phosphorylation of key factors along the TGF-β pathway and the induction of EMT markers. Concomitant with these effects, CJJ300 significantly inhibited cell migration. The present study describes for the first time a designed molecule that can regulate TGF-β-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-β signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-β signaling and to design more potent TGF-β signaling antagonists.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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