Characterization of TAE684 as a potent LRRK2 kinase inhibitor

Jinwei Zhang, Xianming Deng, Hwan Geun Choi, Dario R. Alessi (Lead / Corresponding author), Nathanael S. Gray (Lead / Corresponding author)

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Abstract

Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC50 of 7.8 nM against wild-type LRRK2, 6.1 nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 mu M in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)1864-1869
Number of pages6
JournalBioorganic & Medicinal Chemistry Letters
Volume22
Issue number5
Early online date28 Jan 2012
DOIs
Publication statusPublished - 1 Mar 2012

Keywords

  • Animals
  • Brain
  • Cell Line
  • Cells, Cultured
  • Humans
  • Mice
  • Models, Molecular
  • Mutation
  • Parkinson Disease
  • Protein-Serine-Threonine Kinases
  • Pyrimidines

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