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.

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.