Discovery of novel transforming growth factor β type 1 receptor inhibitors through structure-based virtual screening, preliminary structure–activity relationship study, and biological evaluation in hepatocellular carcinoma

IF 3.3 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic & Medicinal Chemistry Pub Date : 2025-03-26 DOI:10.1016/j.bmc.2025.118175

Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang

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引用次数: 0

Abstract

The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a pivotal role in the tumor microenvironment, making it an attractive target for therapeutic intervention. Small-molecule inhibitors of TGFβR1 offer a promising approach for the treatment of malignant tumors. In this study, a series of 1H-pyrrolo[2,3-b]pyridine derivatives were identified as novel TGFβR1 inhibitors. The most potent candidate, compound 7w, demonstrated inhibition of SMAD2/3 phosphorylation and Hep3B cell viability, with IC₅₀ values of 160.3 nM and 228 μM, respectively. Compound 7w showed a synergistic anti-proliferation and pro-apoptotic effect when combined with sorafenib, highlighting its potential as a promising lead for the development of potential anticancer therapies.

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来源期刊

Bioorganic & Medicinal Chemistry 医学-生化与分子生物学

CiteScore

6.80

自引率

2.90%

发文量

413

审稿时长

17 days

期刊介绍： Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides. The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.