Characterization of a selective inhibitor of the Parkinson's disease kinase LRRK2

Nat Chem Biol. 2011 Apr;7(4):203-5. doi: 10.1038/nchembio.538. Epub 2011 Mar 6.

Abstract

Mutations in leucine-rich repeat kinase 2 (LRRK2) are strongly associated with late-onset autosomal dominant Parkinson's disease. We employed a new, parallel, compound-centric approach to identify a potent and selective LRRK2 inhibitor, LRRK2-IN-1, and demonstrated that inhibition of LRRK2 induces dephosphorylation of Ser910 and Ser935 and accumulation of LRRK2 within aggregate structures. LRRK2-IN-1 will serve as a versatile tool to pharmacologically interrogate LRRK2 biology and study its role in Parkinson's disease.

Publication types

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

MeSH terms

  • Benzodiazepinones / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Mutation
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / chemistry
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyrimidines / pharmacology*
  • Serine / chemistry
  • Serine / metabolism

Substances

  • Benzodiazepinones
  • Enzyme Inhibitors
  • LRRK2-IN1
  • Pyrimidines
  • Serine
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases

Associated data

  • PubChem-Substance/104548353
  • PubChem-Substance/104548354
  • PubChem-Substance/104548355
  • PubChem-Substance/104548356
  • PubChem-Substance/104548357