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

Wu, Han and Sun, Yu and Wong, Wee Lin and Cui, Jiajia and Li, Jingyang and You, Xuefu and Yap, Lee Fah and Huang, Yu and Hong, Wei and Yang, Xinyi and Paterson, Ian Charles and Wang, Hao (2020) The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions. European Journal of Medicinal Chemistry, 189. p. 112042. ISSN 0223-5234, DOI

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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

Item Type: Article
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 )
Uncontrolled Keywords: Transforming growth factor-β inhibitor; TGF-β inhibitor; Protein-protein interactions; Epithelial to mesenchymal transition
Subjects: R Medicine
T Technology > TP Chemical technology
Divisions: Faculty of Dentistry
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 09 Jun 2020 06:22
Last Modified: 09 Jun 2020 06:22

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