Discovery of G2019S-Selective Leucine Rich Repeat Protein Kinase 2 inhibitors with in vivo efficacy

Eur J Med Chem. 2022 Feb 5:229:114080. doi: 10.1016/j.ejmech.2021.114080. Epub 2021 Dec 28.

Abstract

Mutations in the Leucine Rich Repeat Protein Kinase 2 gene (LRRK2) are the most common genetic causes of Parkinson's Disease (PD). The G2019S mutation is the most common inherited LRRK2 mutation, occurs in the kinase domain, and results in increased kinase activity. We report the discovery and development of compound 38, an indazole-based, G2019S-selective (>2000-fold vs. WT) LRRK2 inhibitor capable of entering rodent brain (Kp = 0.5) and selectively inhibiting G2019S-LRRK2. The compounds disclosed herein present a starting point for further development of brain penetrant G2019S selective inhibitors that hopefully reduce lung phenotype side-effects and pave the way to providing a precision medicine for people with PD who carry the G2019S mutation.

Keywords: Kinase inhibitors; LRRK2; Peptides and protein; Rodent models; Selectivity.

MeSH terms

  • Animals
  • Brain
  • Disease Models, Animal
  • Drug Discovery
  • Humans
  • Indazoles / chemical synthesis*
  • Indazoles / pharmacokinetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Lung
  • Male
  • Mice
  • Molecular Docking Simulation
  • Mutation
  • Neuroprotective Agents / chemical synthesis*
  • Neuroprotective Agents / pharmacokinetics
  • Parkinson Disease / drug therapy*
  • Phenotype
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Rodentia
  • Structure-Activity Relationship

Substances

  • Indazoles
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2