Inhibition of TGF-β1/Smad3 signaling by compound 5aa: A potential treatment for idiopathic pulmonary fibrosis

Baijiao An; Yanhua Fang; Lihan Wang; Wenyan Nie; Mengxuan Wang; Haoran Nie; Chengjun Wu; Ruoyu Wang

doi:10.1016/j.bioorg.2024.107374

Inhibition of TGF-β1/Smad3 signaling by compound 5aa: A potential treatment for idiopathic pulmonary fibrosis

Bioorg Chem. 2024 Apr 16:147:107374. doi: 10.1016/j.bioorg.2024.107374. Online ahead of print.

Authors

Baijiao An¹, Yanhua Fang², Lihan Wang³, Wenyan Nie³, Mengxuan Wang³, Haoran Nie³, Chengjun Wu⁴, Ruoyu Wang⁵

Affiliations

¹ The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, Liaoning 116001, China; School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, China; School of Pharmacy, Binzhou Medical University, Yantai, Shandong, 264003, China.
² The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, Liaoning 116001, China.
³ School of Pharmacy, Binzhou Medical University, Yantai, Shandong, 264003, China.
⁴ School of Biomedical Engineering, Dalian University of Technology, Dalian 116024, China. Electronic address: wcj5532@dlut.edu.cn.
⁵ The Key Laboratory of biomarker high throughput screening and target translation of breast and gastrointestinal tumor, Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, Liaoning 116001, China. Electronic address: wangruoyu@dlu.edu.cn.

PMID: 38636433
DOI: 10.1016/j.bioorg.2024.107374

Abstract

The incidence of idiopathic pulmonary fibrosis (IPF) has been steadily increasing each year, posing significant challenges in its treatment. In this study, we conducted the design and synthesis of 23 new inhibitors that specifically target the TGF-β1/Smad3 pathway. Initially, we employed a cell model of TGF-β-induced pulmonary fibrosis, using cell survival rate and HYP expression as indicators to identify the potent ingredient 5aa, which demonstrated significant anti-pulmonary fibrosis activity. Subsequently, we induced mice with bleomycin (BLM) to establish an experimental animal model of pulmonary fibrosis, and evaluated the pharmacodynamics of 5aa in vivo against pulmonary fibrosis. The alterations in HYP and collagen levels in BLM-induced pulmonary fibrosis mice were analyzed using ELISA and immunohistochemistry techniques. The results indicated that compound 5aa effectively suppressed the fibrotic response induced by TGF-β1, inhibited the expression of the fibrotic marker α-SMA, and hindered the EMT process in NIH3T3 cells. Additionally, oral administration of 5aa demonstrated significant therapeutic effects in a mouse model of IPF, comparable to the established drug Nintedanib. Moreover, compound 5aa exhibited higher bioavailability in vivo compared to Nintedanib. These collective outcomes suggest that 5aa holds promise as a potential inhibitor of TGF-β1/Smad3 signaling for the treatment of IPF.

Keywords: IPF; Indolinone derivatives; Nintedanib; Smad3; TGF-β1.