Hatcher John M, Choi Hwan Geun, Alessi Dario R, Gray Nathanael S
Department of Cancer Biology, Dana Farber Cancer Institute, 450 Brookline Ave, Boston, MA, 02215, USA.
New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, 80 Cheombok-ro, Dong-gu, Daegu, 41061, South Korea.
Adv Neurobiol. 2017;14:241-264. doi: 10.1007/978-3-319-49969-7_13.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) protein have been genetically and functionally linked to Parkinson's disease (PD). The kinase activity of LRRK2 is increased by pathogenic mutations; therefore, modulation of LRRK2 kinase activity by a selective small-molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. This chapter presents a historical overview of the development and bioactivity of several small-molecule LRRK2 inhibitors that have been used to inhibit LRRK2 kinase activity in vitro or in vivo. These compounds are important tools for understanding the cellular biology of LRRK2 and for evaluating the potential of LRRK2 inhibitors as disease-modifying PD therapies.
富含亮氨酸重复激酶2（LRRK2）蛋白的突变在基因和功能上与帕金森病（PD）相关联。致病性突变会增加LRRK2的激酶活性；因此，有人提出用选择性小分子抑制剂调节LRRK2激酶活性作为帕金森病一种潜在可行的治疗方法。本章对几种小分子LRRK2抑制剂的研发和生物活性进行了历史概述，这些抑制剂已被用于在体外或体内抑制LRRK2激酶活性。这些化合物是理解LRRK2细胞生物学以及评估LRRK2抑制剂作为疾病修饰性帕金森病疗法潜力的重要工具。
