Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1) PMID: 29023112

ADC Targets in Oncology

2026-04-10

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.

Douglas S Williamson ¹ , Garrick P Smith ² , Pamela Acheson-Dossang ¹ , Simon T Bedford ¹ , Victoria Chell ¹ , I-Jen Chen ¹ , Justus C A Daechsel ² , Zoe Daniels ¹ , Laurent David ² , Pawel Dokurno ¹ , Morten Hentzer ² , Martin C Herzig ² , Roderick E Hubbard ¹ , Jonathan D Moore ¹ , James B Murray ¹ , Samantha Newland ¹ , Stuart C Ray ¹ , Terry Shaw ¹ , Allan E Surgenor ¹ , Lindsey Terry ¹ , Kenneth Thirstrup ¹ , Yikang Wang ¹ , Kenneth V Christensen ²

Affiliations

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 LRRK2-pSer935 IC₅₀ values for 22 in mouse brain and kidney being 1.3 and 5 nM, respectively.