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

Siyuan Liu; Fusheng Wang; Caifang Zhang; Hong Jiang; Chun Liu

doi:10.1016/j.bioorg.2025.108156

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. Epub 2025 Jan 10.

Authors

Siyuan Liu¹, Fusheng Wang², Caifang Zhang³, Hong Jiang⁴, Chun Liu⁵

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.

MeSH terms

Animals
Antineoplastic Agents* / chemical synthesis
Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Apoptosis / drug effects
Carcinoma, Hepatocellular* / drug therapy
Carcinoma, Hepatocellular* / metabolism
Carcinoma, Hepatocellular* / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor*
Humans
Liver Neoplasms* / drug therapy
Liver Neoplasms* / pathology
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology
Quinolines* / chemical synthesis
Quinolines* / chemistry
Quinolines* / pharmacology
Receptor, Transforming Growth Factor-beta Type I* / antagonists & inhibitors
Receptor, Transforming Growth Factor-beta Type I* / metabolism
Structure-Activity Relationship

Substances

Receptor, Transforming Growth Factor-beta Type I
Quinolines
Antineoplastic Agents
Protein Kinase Inhibitors
Pyrazoles