Göring Stefan, Taymans Jean-Marc, Baekelandt Veerle, Schmidt Boris
Clemens Schöpf-Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, 64287 Darmstadt, Hessen, Germany.
KU Leuven, Laboratory for Neurobiology and Gene Therapy, Leuven B-3000, Belgium.
Bioorg Med Chem Lett. 2014 Oct 1;24(19):4630-4637. doi: 10.1016/j.bmcl.2014.08.049. Epub 2014 Aug 29.
The most prevalent leucine-rich repeat kinase 2 (LRRK2) mutation G2019S is associated with Parkinson's disease (PD). It enhances kinase activity and has been identified in both familial and sporadic cases. Kinase activity was reported to be required for LRRK2 mutants to exert their toxic effects. Hence LRRK2 kinase inhibition may be a promising therapeutic target for PD. Here we report on the discovery and characterization of indolinone based LRRK2 inhibitors. Indolinone 15b, the most potent and selective inhibitor of the present series, is characterized by an IC50 of 15nM against wild-type LRRK2 and 10nM against the LRRK2 G2019S mutant, respectively. Compound 15b was further evaluated in a kinase panel including 46 human protein kinases and in a zebrafish embryo phenotype assay, which enabled toxicity determination in whole organisms.
最常见的富含亮氨酸重复序列激酶2（LRRK2）突变G2019S与帕金森病（PD）相关。它增强激酶活性，已在家族性和散发性病例中被发现。据报道，LRRK2突变体发挥其毒性作用需要激酶活性。因此，抑制LRRK2激酶可能是治疗PD的一个有前景的靶点。在此，我们报告基于吲哚酮的LRRK2抑制剂的发现和特性。吲哚酮15b是本系列中最有效和选择性最高的抑制剂，其对野生型LRRK2的IC50分别为15nM，对LRRK2 G2019S突变体的IC50为10nM。化合物15b在包含46种人类蛋白激酶的激酶组以及斑马鱼胚胎表型试验中进一步评估，该试验能够在整个生物体中确定毒性。
