2. Academic Validation
  3. Synthesis and biological evaluation of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives as novel potential transforming growth factor-β type 1 receptor inhibitors for hepatocellular carcinoma

Synthesis and biological evaluation of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives as novel potential transforming growth factor-β type 1 receptor inhibitors for hepatocellular carcinoma

  • Bioorg Chem. 2025 Feb:155:108156. doi: 10.1016/j.bioorg.2025.108156.
Siyuan Liu 1,  Fusheng Wang 2,  Caifang Zhang 3,  Hong Jiang 4,  Chun Liu 5
Affiliations

Affiliations

  • 1 Department of General Surgery, the Second Xiang-Ya Hospital, Central South University, Changsha 410011 China; The First Central Clinical School, Tianjin Medical University, Tianjin 300190 China.
  • 2 Department of General Surgery, Fuyang People's Hospital, Fuyang China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 4 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
  • 5 Department of General Surgery, the Second Xiang-Ya Hospital, Central South University, Changsha 410011 China. Electronic address: liuchun504@csu.edu.cn.
PMID: 39809119 DOI: 10.1016/j.bioorg.2025.108156
Abstract

The transforming growth factor β (TGF-β) type 1 receptor (ALK5) plays a key role in tumor microenvironment. Small-molecule inhibitors of TGFβR1 provides a prospective approach for the treatment of malignant tumors. In this study, a series of 4-((3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)oxy)quinoline derivatives were identified as novel, potential TGFβR1 inhibitors. The most potent compound 16w inhibited SMAD2/3 phosphorylation and H22 cell viability with IC50 values of 12 and 65 nM, respectively. Further, compound 16w exhibited reasonable pharmacokinetic profiles and exhibited significant anti-tumor efficacy in a xenograft model of H22 cells, with TGI of 79.6 %. Additionally, compound 16w also showed a strong synergistic proapoptotic effect in combination with sorafenib, which provided a promising lead for further development of novel Anticancer drugs.

Keywords

Galunisertib; H22 xenograft model; Hepatocellular carcinoma; Transforming growth factor β.

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