Synthesis and anti-tumor activity of imidazopyrazines as TAK1 inhibitors

Eur J Med Chem. 2019 Feb 1:163:660-670. doi: 10.1016/j.ejmech.2018.12.025. Epub 2018 Dec 13.

Abstract

Transforming growth factor-β activated kinase-1 (TAK1) is a potential therapeutic target for cancers and inflammatory diseases. We synthesized a series of novel imidazopyrazine derivatives, which were found to exhibit potent inhibitory effect against TAK1. Compound 22a, which possesses a good pharmacokinetic profile, showed excellent in vitro kinase activity and significant in vivo efficacy in mice xenografted with SW620, a KRAS-dependent colon cancer cell line.

Keywords: Colon cancer; Imidazopyrazine; TAK1.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / pathology
  • Heterografts
  • Humans
  • Inflammation / drug therapy
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Mice
  • Neoplasms / drug therapy
  • Protein Kinase Inhibitors / chemistry*
  • Pyrazines / chemical synthesis
  • Pyrazines / pharmacokinetics
  • Pyrazines / pharmacology
  • Pyrazines / therapeutic use*

Substances

  • Protein Kinase Inhibitors
  • Pyrazines
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7