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

DOI: 10.1021/acs.jmedchem.7b01186 DOI Help

Authors: Douglas S. Williamson (Vernalis (R&D) Ltd) , Garrick P. Smith (H. Lundbeck A/S) , Pamela Acheson-dossang (Vernalis (R&D) Ltd) , Simon T. Bedford (Vernalis (R&D) Ltd) , Victoria Chell (Vernalis (R&D) Ltd) , I-jen Chen (Vernalis (R&D) Ltd) , Justus C. A. Daechsel (H. Lundbeck A/S) , Zoe Daniels (Vernalis (R&D) Ltd) , Laurent David (H. Lundbeck A/S) , Pawel Dokurno (Vernalis (R&D) Ltd) , Morten Hentzer (H. Lundbeck A/S) , Martin C. Herzig (H. Lundbeck A/S) , Roderick E. Hubbard (Vernalis (R&D) Ltd) , Jonathan D. Moore (Vernalis (R&D) Ltd) , James B. Murray (Vernalis (R&D) Ltd) , Samantha Newland (Vernalis (R&D) Ltd) , Stuart C. Ray (Vernalis (R&D) Ltd) , Terry Shaw (Vernalis (R&D) Ltd) , Allan E. Surgenor (Vernalis (R&D) Ltd) , Lindsey Terry (Vernalis (R&D) Ltd) , Kenneth Thirstrup (Vernalis (R&D) Ltd) , Yikang Wang (Vernalis (R&D) Ltd) , Kenneth V. Christensen (H. Lundbeck A/S)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: October 2017
Diamond Proposal Number(s): 5791 , 12428 , 2103 , 14641 , 5067

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-pt. mut. 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 nM and 5 nM, respectively.

Journal Keywords: Parkinson's disease; PD, leucine-rich repeat kinase 2; LRRK2, kinase inhibitor; checkpoint kinase 1; CHK1, mutant; CHK1 10-pt. mut.; surrogate; pyrrolo[2,3-b]pyridine

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography