Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1)

J Med Chem. 2017 Nov 9;60(21):8945-8962. doi: 10.1021/acs.jmedchem.7b01186. Epub 2017 Oct 27.


Mutations in leucine-rich repeat kinase 2 (LRRK2), such as G2019S, are associated with an increased risk of developing Parkinson's disease. Surrogates for the LRRK2 kinase domain based on checkpoint kinase 1 (CHK1) mutants were designed, expressed in insect cells infected with baculovirus, purified, and crystallized. X-ray structures of the surrogates complexed with known LRRK2 inhibitors rationalized compound potency and selectivity. The CHK1 10-point mutant was preferred, following assessment of surrogate binding affinity with LRRK2 inhibitors. Fragment hit-derived arylpyrrolo[2,3-b]pyridine LRRK2 inhibitors underwent structure-guided optimization using this crystallographic surrogate. LRRK2-pSer935 HEK293 IC50 data for 22 were consistent with binding to Ala2016 in LRRK2 (equivalent to Ala147 in CHK1 10-point mutant structure). Compound 22 was shown to be potent, moderately selective, orally available, and brain-penetrant in wild-type mice, and confirmation of target engagement was demonstrated, with LRRK2-pSer935 IC50 values for 22 in mouse brain and kidney being 1.3 and 5 nM, respectively.

MeSH terms

  • Animals
  • Brain / metabolism
  • Checkpoint Kinase 1
  • Crystallography / methods
  • HEK293 Cells
  • Humans
  • Kidney / metabolism
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / antagonists & inhibitors*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Mice
  • Mutation
  • Parkinson Disease / genetics
  • Protein Binding
  • Protein Domains
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / therapeutic use*


  • Protein Kinase Inhibitors
  • Checkpoint Kinase 1
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2