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

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

Affiliations

  • 1 Vernalis (R&D) Ltd. , Granta Park, Great Abington, Cambridge, CB21 6GB, United Kingdom.
  • 2 H. Lundbeck A/S , Ottiliavej 9, 2500 Valby, Denmark.
PMID: 29023112 DOI: 10.1021/acs.jmedchem.7b01186
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z