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The Tyr-kinase inhibitor AG879, that blocks the ETK-PAK1 interaction, suppresses the RAS-induced PAK1 activation and

Hong He1, Yumiko Hirokawa, Aviv Gazit

  • 1Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Parkville/Melbourne, Australia.

Cancer Biology & Therapy
|January 17, 2004
PubMed

Insights

The tyrosine kinase inhibitor AG 879 blocks the ETK-PAK1 pathway at low concentrations, impacting cell growth. This suggests AG 879 targets a kinase upstream of ETK, aiding in identifying its primary target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • AG 879 is a known tyrosine kinase inhibitor targeting ErbB2 and FLK-1.
  • AG 879, combined with PP1, inhibits RAS-induced sarcoma growth in mice.
  • The ETK-PAK1 interaction is crucial for RAS-induced PAK1 activation and fibroblast transformation.

Purpose of the Study:

  • To investigate the mechanism by which AG 879 affects the ETK-PAK1 pathway.
  • To determine the effective concentration of AG 879 in blocking ETK-PAK1 interaction.
  • To identify the upstream kinase targeted by AG 879.

Main Methods:

  • Cell culture experiments to assess AG 879's effect on ETK-PAK1 interaction.
  • In vitro kinase assays using purified ETK and PAK1.
  • Structure-function analysis of AG 879 derivatives.

Main Results:

  • AG 879 at 10 nM inhibits the ETK-PAK1 interaction in cell culture.
  • AG 879 does not directly inhibit purified ETK or PAK1 in vitro.
  • AG 879's thio and tert-butyl groups are essential for blocking the ETK-PAK1 pathway.

Conclusions:

  • AG 879 likely targets a kinase upstream of ETK to inhibit the ETK-PAK1 pathway.
  • The structure of AG 879 allows for the creation of affinity ligands to identify its primary target.
  • AG 879's specific action on the ETK-PAK1 pathway offers potential therapeutic insights.

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