2. Academic Validation
  3. 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

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

  • Bioorg Med Chem. 2025 Jun 1:123:118175. doi: 10.1016/j.bmc.2025.118175.
Siyuan Liu 1,  Jian Yu 2,  Xinrao Du 3,  Haizhou Hao 4,  Xinyue Xie 5,  Abdisamat Ababakri 6,  Junyan Zhang 7,  Li Zhang 8,  Jisan Sun 9,  Yan Xie 10,  Wentao Jiang 11
Affiliations

Affiliations

  • 1 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: lsy940420@163.com.
  • 2 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: Johnny97@yeah.net.
  • 3 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: DuXinRao857@tmu.edu.cn.
  • 4 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: livertransHHZ@tmu.edu.cn.
  • 5 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: 13231712021@163.com.
  • 6 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: 1491792590@qq.com.
  • 7 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: 1301865889@qq.com.
  • 8 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: tjzhli@126.com.
  • 9 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: sunjs1980@nankai.edu.cn.
  • 10 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: dr.xieyan@nankai.edu.cn.
  • 11 First Central Clinical School, Tianjin Medical University, Tianjin 300070, China; Tianjin Key Laboratory of Molecular Diagnosis and Treatment of Liver Cancer, Tianjin First Center Hospital, Tianjin 300192, China; Liver Transplantation Department, Tianjin First Center Hospital, Tianjin China. Electronic address: jwt001@163.com.
PMID: 40163974 DOI: 10.1016/j.bmc.2025.118175
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.

Keywords

Galunisertib; Hepatocellular carcinoma; Sorafenib; Transforming growth factor β.

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