Characterization of TAE684 as a potent LRRK2 kinase inhibitor

Bioorg Med Chem Lett. 2012 Mar 1;22(5):1864-9. doi: 10.1016/j.bmcl.2012.01.084. Epub 2012 Jan 28.

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 (IC(50) of 7.8nM against wild-type LRRK2, 6.1nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3μM in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10mg/kg.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / enzymology
  • Brain / metabolism
  • Cell Line
  • Cells, Cultured
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mice
  • Models, Molecular
  • Mutation
  • Parkinson Disease / drug therapy
  • Parkinson Disease / enzymology*
  • Parkinson Disease / genetics
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyrimidines / pharmacology*

Substances

  • NVP-TAE684
  • Pyrimidines
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Lrrk2 protein, mouse
  • Protein-Serine-Threonine Kinases