School of Medical Sciences, University of Sydney, NSW 2006, Australia.
School of Chemistry, University of Sydney, NSW 2006, Australia.
Eur J Med Chem. 2015 May 5;95:29-34. doi: 10.1016/j.ejmech.2015.03.003. Epub 2015 Mar 3.
LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM; 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 μM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show anti-neuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti-neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL-1β stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes.
LRRK2IN1 是一种强效的富亮氨酸重复激酶 2（LRRK2，IC50=7.9 nM）抑制剂，是治疗帕金森病的既定靶点。合成了两种保留 LRRK2 抑制活性的 LRRK2IN1 类似物 1 和 2（1：IC50=72 nM；2：IC50=51 nM），预计具有更好的生物利用度，并在神经炎症的基于细胞的模型中有效。类似物 1 以 EC50=4.26 μM 的浓度抑制 LPS 刺激的原代人小胶质细胞中 IL-6 的分泌。为了进一步优化 LRRK2IN1 的分子特性，根据对接研究设计了一个截断类似物文库。尽管这些化合物缺乏 LRRK2 抑制活性，但它们在微摩尔浓度下表现出抗神经炎症活性。开发的化合物是建立基于细胞的测定法以评估 LRRK2 抑制剂的抗神经炎症功效的有价值的工具。本文提供的数据表明，IL-1β 刺激的 U87 神经胶质瘤细胞系是神经炎症的可靠模型，因为该模型中获得的数据与使用原代人小胶质细胞和星形胶质细胞获得的结果一致。
