鉴定 TAE684 是一种强效的 LRRK2 激酶抑制剂。
Characterization of TAE684 as a potent LRRK2 kinase inhibitor.
机构信息
MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
出版信息
Bioorg Med Chem Lett. 2012 Mar 1;22(5):1864-9. doi: 10.1016/j.bmcl.2012.01.084. Epub 2012 Jan 28.
Abstract
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 (IC(50) of 7.8nM against wild-type LRRK2, 6.1nM against the G2019S mutant). TAE684 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3μM in cells and in mouse spleen and kidney, but not in brain, following oral doses of 10mg/kg.
摘要
富含亮氨酸重复激酶 2（LRRK2）与帕金森病有关，可能是一个有吸引力的治疗靶点。在此，我们报告一种 2,4-二苯胺基-5-氯嘧啶，TAE684，它是一种先前报道的间变性淋巴瘤激酶（ALK）抑制剂，也是 LRRK2 激酶活性的有效抑制剂（对野生型 LRRK2 的 IC50 为 7.8nM，对 G2019S 突变体的 IC50 为 6.1nM）。TAE684 在细胞内和小鼠脾和肾中，以 0.1-0.3μM 的浓度显著抑制野生型 LRRK2 和 G2019S 突变体 Ser910 和 Ser935 的磷酸化，但在脑内没有作用，在口服剂量为 10mg/kg 时也是如此。
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