Brigham & Women's Hospital, 65 Landsdowne Street, Fourth Floor, Cambridge, MA 02139, USA.
Future Med Chem. 2012 Sep;4(13):1701-13. doi: 10.4155/fmc.12.110.
Since leucine-rich repeat kinase 2 (LRRK2) was linked to Parkinson's disease in 2004, kinase activity of LRRK2 has been believed to play a critical role in the pathogenesis of Parkinson's disease. As a result, identification of LRRK2 inhibitors has been a focus for drug discovery. However, most LRRK2 mutations do not simply increase kinase activity. In this review we summarize the potential mechanisms that regulate the kinase activity of LRRK2. We outline some currently available kinase inhibitors, including the identification of a DFG-out (type-II) inhibitor. Finally, we discuss the relationship of LRRK2 with tau and α-synuclein. The fact that all three proteins are autophapgy-related provides a future strategy for the identification of LRRK2 physiological substrate(s).
自 2004 年富含亮氨酸重复激酶 2（LRRK2）与帕金森病相关以来，LRRK2 的激酶活性被认为在帕金森病的发病机制中起关键作用。因此，寻找 LRRK2 抑制剂一直是药物发现的重点。然而，大多数 LRRK2 突变并不能简单地增加激酶活性。在这篇综述中，我们总结了调节 LRRK2 激酶活性的潜在机制。我们概述了一些目前可用的激酶抑制剂，包括鉴定出的一种 DFG-out（II 型）抑制剂。最后，我们讨论了 LRRK2 与 tau 和 α-突触核蛋白的关系。这三种蛋白均与自噬有关，这为鉴定 LRRK2 的生理底物提供了一个未来的策略。
