Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang
{"title":"通过基于结构的虚拟筛选、初步构效关系研究和肝细胞癌生物学评价发现新的转化生长因子β 1型受体抑制剂","authors":"Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang","doi":"10.1016/j.bmc.2025.118175","DOIUrl":null,"url":null,"abstract":"<div><div>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 1<em>H</em>-pyrrolo[2,3-<em>b</em>]pyridine derivatives were identified as novel TGFβR1 inhibitors. The most potent candidate, compound <strong>7w</strong>, demonstrated inhibition of SMAD2/3 phosphorylation and Hep3B cell viability, with IC<sub>50</sub> values of 160.3 nM and 228 μM, respectively. Compound <strong>7w</strong> 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.</div></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"123 ","pages":"Article 118175"},"PeriodicalIF":3.0000,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"Siyuan Liu , Jian Yu , Xinrao Du , Haizhou Hao , Xinyue Xie , Abdisamat Ababakri , Junyan Zhang , Li Zhang , Jisan Sun , Yan Xie , Wentao Jiang\",\"doi\":\"10.1016/j.bmc.2025.118175\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 1<em>H</em>-pyrrolo[2,3-<em>b</em>]pyridine derivatives were identified as novel TGFβR1 inhibitors. The most potent candidate, compound <strong>7w</strong>, demonstrated inhibition of SMAD2/3 phosphorylation and Hep3B cell viability, with IC<sub>50</sub> values of 160.3 nM and 228 μM, respectively. Compound <strong>7w</strong> 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.</div></div>\",\"PeriodicalId\":255,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry\",\"volume\":\"123 \",\"pages\":\"Article 118175\"},\"PeriodicalIF\":3.0000,\"publicationDate\":\"2025-03-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0968089625001166\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089625001166","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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
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.
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.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
