4-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2-yl)imidazole and -pyrazole derivatives as potent and selective inhibitors of transforming growth factor-β type i receptor kinase

Cheng Hua Jin, Maddeboina Krishnaiah, Domalapally Sreenu, Vura Bala Subrahmanyam, Hyun Ju Park, So Jung Park, Yhun Yhong Sheen, Dae Kee Kim

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

A series of 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5(3)-(6-methylpyridin-2- yl)imidazoles and -pyrazoles 14a-c, 15a-c, 16a, 16b, 19a-d, 21a, and 21b has been synthesized and evaluated for their ALK5 inhibitory activity in an enzyme assay and in a cell-based luciferase reporter assay. Among them, the pyrazole derivative 21b inhibited ALK5 phosphorylation with an IC50 value of 0.018 μM and showed 95% inhibition at 0.03 μM in a luciferase reporter assay using HaCaT cells permanently transfected with p3TP-luc reporter construct. The 21b showed a high selectivity index of 284 against p38α MAP kinase. The binding pose of 21b generated by docking analysis reveals that it fits well into the ATP binding cavity of ALK5 by forming several hydrogen bond interactions.

Original languageEnglish
Pages (from-to)2724-2732
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number9
DOIs
StatePublished - 1 May 2014

Bibliographical note

Funding Information:
This work was supported by RP-Grant 2011 of Ewha Womans University.

Keywords

  • ALK5 inhibitor
  • Cancer
  • Cell-based luciferase reporter assay
  • Docking
  • Fibrosis
  • Kinase assay
  • TGF-β

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