ACS Chem Biol. 2011 Oct 21;6(10):1021-8. doi: 10.1021/cb2002413. Epub 2011 Aug 10.
Leucine-rich repeat kinase-2 (LRRK2) mutations are the most important cause of familial Parkinson's disease, and non-selective inhibitors are protective in rodent disease models. Because of their poor potency and selectivity, the neuroprotective mechanism of these tool compounds has remained elusive so far, and it is still unknown whether selective LRRK2 inhibition can attenuate mutant LRRK2-dependent toxicity in human neurons. Here, we employ a chemoproteomics strategy to identify potent, selective, and metabolically stable LRRK2 inhibitors. We demonstrate that CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency. These precise chemical probes further validate this emerging therapeutic strategy. They will enable more detailed studies of LRRK2-dependent signaling and pathogenesis and accelerate drug discovery.
富含亮氨酸重复激酶 2（LRRK2）突变是家族性帕金森病的最重要原因，而非选择性抑制剂在啮齿动物疾病模型中具有保护作用。由于这些工具化合物的效力和选择性较差，迄今为止，其神经保护机制仍难以捉摸，并且尚不清楚选择性 LRRK2 抑制是否可以减轻人神经元中突变 LRRK2 依赖性毒性。在这里，我们采用化学生物学策略来鉴定有效、选择性和代谢稳定的 LRRK2 抑制剂。我们证明 CZC-25146 以中纳摩尔效力预防突变 LRRK2 诱导的培养的啮齿动物和人类神经元损伤。这些精确的化学探针进一步验证了这种新兴的治疗策略。它们将能够更详细地研究 LRRK2 依赖性信号传导和发病机制，并加速药物发现。
