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Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1)
- Source :
- Journal of Medicinal Chemistry. 60:8945-8962
- Publication Year :
- 2017
- Publisher :
- American Chemical Society (ACS), 2017.
-
Abstract
- 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 LR...
- Subjects :
- 0301 basic medicine
Protein domain
Mutant
Leucine-rich repeat
Kidney
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
01 natural sciences
Mice
03 medical and health sciences
Protein Domains
Drug Discovery
Animals
Humans
CHEK1
Protein Kinase Inhibitors
Crystallography
010405 organic chemistry
Chemistry
Kinase
Brain
Kidney metabolism
Parkinson Disease
LRRK2
Molecular biology
nervous system diseases
0104 chemical sciences
HEK293 Cells
030104 developmental biology
Protein kinase domain
Biochemistry
Checkpoint Kinase 1
Mutation
Molecular Medicine
Protein Binding
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....de891ae3a7927d47b4fdf8368236edb1