The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions
Document Type
Article
Publication Date
1-1-2020
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. © 2020 Elsevier Masson SAS
Keywords
Transforming growth factor-β inhibitor, TGF-β inhibitor, Protein-protein interactions, Epithelial to mesenchymal transition
Divisions
Dentistry
Funders
National Natural Science Foundation of China ( 81660588 , 81960623 , 81773582 , 81973383 ),Key R&D Program of Ningxia, China ( 2018BFG02004 ),Program for Leading Talents of Ningxia Province, China ( KJT2018004 ),National Mega-project for Innovative Drugs, China ( 2019ZX09721001 ),Beijing Science and Technology Projects, China ( Z141102004414065 and Z151100000315029 ),CAMS Initiative Fund for Innovative Medicine, China ( 2016-I2M-3-014 ),Peking Union Medical College (PUMC) Youth Fund, China ( 33320140177 and 3332016139 )
Publication Title
European Journal of Medicinal Chemistry
Volume
189
Publisher
Elsevier