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

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.