Small molecule kinase inhibitors for LRRK2 and their application to Parkinson's disease models

ACS Chem Neurosci. 2012 Mar 21;3(3):151-60. doi: 10.1021/cn200117j. Epub 2012 Jan 18.

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Several single gene mutations have been linked to this disease. Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) indicate LRRK2 as promising therapeutic target for the treatment of PD. LRRK2 mutations were observed in sporadic as well as familial PD patients and have been investigated intensively. LRRK2 is a large and complex protein, with multiple enzymatic and protein-interaction domains, each of which is effected by mutations. The most common mutation in PD patients is G2019S. Several LRRK2 inhibitors have been reported already, although the crystal structure of LRRK2 has not yet been determined. This review provides a summary of known LRRK2 inhibitors and will discuss recent in vitro and in vivo results of these inhibitors.

Keywords: LRRK2 inhibitors; Parkinson's disease; animal models; leucine-rich repeat kinase 2 (LRRK2); mutations.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Disease Models, Animal*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / enzymology*
  • Parkinson Disease / genetics
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism

Substances

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