Characterization of TAE684 as a potent LRRK2 kinase inhibitor

TY - JOUR

T1 - Characterization of TAE684 as a potent LRRK2 kinase inhibitor

A1 - Zhang,Jinwei

A1 - Deng,Xianming

A1 - Choi,Hwan Geun

A1 - Alessi,Dario R.

A1 - Gray,Nathanael S.

AU - Zhang,Jinwei

AU - Deng,Xianming

AU - Choi,Hwan Geun

AU - Alessi,Dario R.

AU - Gray,Nathanael S.

PY - 2012/3/1

Y1 - 2012/3/1

N2 - <p>Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC50 of 7.8 nM against wild-type LRRK2, 6.1 nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 mu M in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved.</p>

AB - <p>Leucine-rich repeat kinase 2 (LRRK2) is linked to Parkinson's disease and may represent an attractive therapeutic target. Here we report a 2,4-dianilino-5-chloro-pyrimidine, TAE684, a previously reported inhibitor of anaplastic lymphoma kinase (ALK), is also a potent inhibitor of LRRK2 kinase activity (IC50 of 7.8 nM against wild-type LRRK2, 6.1 nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 mu M in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10 mg/kg. (c) 2012 Elsevier Ltd. All rights reserved.</p>

KW - Parkinson's disease

KW - LRRK2

KW - TAE684

U2 - 10.1016/j.bmcl.2012.01.084

DO - 10.1016/j.bmcl.2012.01.084

M1 - Article

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

SN - 0960-894X

IS - 5

VL - 22

SP - 1864

EP - 1869

ER -