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

被引：36

作者：

Williamson, Douglas S. ^{[1
]}

Smith, Garrick P. ^{[2
]}

Acheson-Dossan, Pamela ^{[1
]}

Bedford, Simon T. ^{[1
]}

Chell, Victoria ^{[1
]}

Chen, I-Jen ^{[1
]}

Daechsel, Justus C. A. ^{[2
]}

Daniels, Zoe ^{[1
]}

David, Laurent ^{[2
]}

Dokurno, Pawel ^{[1
]}

Hentzer, Morten ^{[2
]}

Herzig, Martin C. ^{[2
]}

Hubbard, Roderick E. ^{[1
]}

Moore, Jonathan D. ^{[1
]}

Murray, James B. ^{[1
]}

Newland, Samantha ^{[1
]}

Ray, Stuart C. ^{[1
]}

Shaw, Terry ^{[1
]}

Surgenor, Allan E. ^{[1
]}

Terry, Lindsey ^{[1
]}

Thirstrup, Kenneth ^{[1
]}

Wang, Yikang ^{[1
]}

Christensen, Kenneth V. ^{[2
]}

机构：

[1] Vernalis R&D Ltd, Granta Pk, Cambridge CB21 6GB, England

[2] H Lundbeck & Co AS, Ottiliavej 9, DK-2500 Valby, Denmark

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 21期

关键词：

PARKINSONS-DISEASE; BRAIN-PENETRANT; HIGHLY POTENT; DISCOVERY; IDENTIFICATION; FEATURES; MUTATIONS; THERAPIES; ENSEMBLE; INSIGHTS;

D O I：

10.1021/acs.jmedchem.7b01186

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 A1a2016 in LRRK2 (equivalent to A1a147 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.

引用

页码：8945 / 8962

页数：18

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