3-取代吲哚-2-酮类化合物对抗帕金森病的多靶点机制研究

3-取代吲哚-2-酮类化合物已用于临床肿瘤治疗。我们前期工作首次发现该类化合物可对抗多巴胺能神经元凋亡和动物运动障碍，可望用于帕金森病（PD）治疗。富亮氨酸重复激酶2（LRRK2）是PD主要突变基因、肌细胞增强因子2（MEF2）是促多巴胺能神经元存活的关键转录因子，它们已被证实是抗PD神经保护的重要靶点。申请人发现部分3-取代吲哚-2-酮类化合物可抑制LRRK2激酶活性、增强MEF2转录活性，提示该类化合物可能多靶点对抗PD。本项目将首先应用体外活性检测、计算机分子对接等方法明确该类化合物对LRRK2、MEF2等靶点的活性以及构效关系；进一步在PD细胞模型明确其多靶点神经保护的分子机制。研究有望获得一类结构全新、靶点明确、机制清晰的抗PD先导化合物，为将3-取代吲哚-2-酮类化合物发展成抗PD药物提供科学依据。

3-substituted indolin-2-ones are currently used in the clinical treatment of cancer. We have previously discovered that 3-substituted indolin-ones could protect against dopaminergic neuronal death and motor dysfunction in vivo, suggesting that these compounds may also be used to treat Parkinson's disease (PD). Leucine rich repeat kinase 2 (LRRK2) is a main gene mutated in PD. Myocyte enhancer factor 2 (MEF2) is an important transcriptional factor for the survival of dopaminergic neurons. Both LRRK2 and MEF2 are proven to be key targets for anti-PD neuroprotective drugs. We found that some 3-substitited indolin-2-ones could directly inhibit kinase activity of LRRK2 and enhance transcriptional activity of MEF2, indicating that these compounds may produce anti-PD effects via multiple targets. In this application, we would first investigate the structural-activity relationship of 3-substituted indolin-2-ones on the inhibition of LRRK2 and the activation of MEF2 by using in vitro system and molecular docking analysis. Moreover, we would explore the multi-target mechanisms underlying the neuroprotective effects of these compounds. Our study might provide a group of novel multi-target anti-PD leads.