The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions
The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions
复制标题
开发一种新型转化生长因子-β (TGF-β) 抑制剂，可破坏配体-受体相互作用
DOI：
10.1016/j.ejmech.2020.112042
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发表时间：
2020-03-01
影响因子：
6.7
通讯作者：
Wang, Hao
中科院分区：
文献类型：
--
作者：
Wu, Han;Sun, Yu;Wang, Hao
转化生长因子-β (TGF-β) 在调节上皮间质转化 (EMT) 中发挥着重要作用，TGF-β 信号通路是纤维化和癌症等许多疾病发展过程中治疗干预的潜在靶点。目前大多数可用的 TGF-β 信号传导抑制剂均作为 TGF-β 受体 I (T beta R-I) 激酶抑制剂发挥作用，然而，此类激酶抑制剂通常缺乏特异性。在本研究中，我们以 TGF-β 受体 II (T beta R-II) 的胞外蛋白结合域为目标，干扰 TGF-β 与其受体之间的蛋白质-蛋白质相互作用 (PPI)。一种化合物 CJJ300 通过破坏 TGF-β-T beta R-I-T beta R-II 信号复合物的形成来抑制 TGF-β 信号传导。用 CJJ300 处理 A549 细胞会抑制下游信号转导事件，例如 TGF-β 途径关键因子的磷酸化和 EMT 标记物的诱导。伴随这些作用，CJJ300 显着抑制细胞迁移。本研究首次描述了一种设计的分子，该分子可以通过干扰 TGF-β 信号复合物形成所需的 PPI 来调节 TGF-β 诱导的信号传导和 EMT。因此，CJJ300 可以成为研究 TGF-β 信号传导和设计更有效的 TGF-β 信号传导拮抗剂的重要先导化合物。 (C) 2020 Elsevier Masson SAS。版权所有。
Transforming growth factor-beta (TGF-beta) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-beta 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-beta signaling function as TGF-beta receptor I (T beta R-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-beta receptor II (T beta R-II) to interfere with the protein-protein interactions (PPIs) between TGF-beta and its receptors. One compound, CJJ300, inhibited TGF-beta signaling by disrupting the formation of the TGF-beta-T beta R-I-T beta R-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-beta 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-beta-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-beta signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-beta signaling and to design more potent TGF-beta signaling antagonists. (C) 2020 Elsevier Masson SAS. All rights reserved.