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
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
  • 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: [email protected].
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.
Products