Synthesis and Evaluation of 3-Substituted-4-(quinoxalin-6-yl) Pyrazoles as TGF-β Type I Receptor Kinase Inhibitors

Molecules. 2018 Dec 19;23(12):3369. doi: 10.3390/molecules23123369.


The transforming growth factor-β (TGF-β), in which overexpression has been associated with various diseases, has become an attractive molecular target for the treatment of cancers. Thirty-two quinoxaline-derivatives of 3-substituted-4-(quinoxalin-6-yl) pyrazoles 14ad, 15ad, 16ad, 17ad, 18ad, 19ad, 25a, 25b, 25d, 26a, 26b, 26d, 27b, and 27d were synthesized and evaluated for their activin TGF-β type I receptor kinase and p38α mitogen activated protein (MAP) kinase inhibitory activity in enzymatic assays. Among these compounds, the most active compound 19b inhibited TGF-β type I receptor kinase phosphorylation with an IC50 value of 0.28 µM, with 98% inhibition at 10 µM. Compound 19b also had good selectivity index of >35 against p38α MAP kinase, with 9.0-fold more selective than clinical candidate, compound 3 (LY-2157299). A molecular docking study was performed to identify the mechanism of action of the synthesized compounds and their good binding interactions were observed. ADMET prediction of good active compounds showed that these ones possess good pharmacokinetics and drug-likeness behavior.

Keywords: ALK5 inhibitor; TGF-β; docking; kinase assay; selectivity.

MeSH terms

  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Molecular Docking Simulation
  • Pyrazoles / chemistry*
  • Quinolines / chemistry
  • Receptor, Transforming Growth Factor-beta Type I / antagonists & inhibitors*
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Pyrazoles
  • Quinolines
  • LY-2157299
  • Receptor, Transforming Growth Factor-beta Type I