Christensen K V, Smith G P, Williamson D S
Neuroscience Drug Discovery, H. Lundbeck A/S, Valby, Denmark.
Vernalis (R&D) Ltd, Cambridge, United Kingdom.
Prog Med Chem. 2017;56:37-80. doi: 10.1016/bs.pmch.2016.11.002. Epub 2017 Jan 4.
Linkage and genome-wide association studies have identified a genetic risk locus for late-onset Parkinson's disease in chromosome 12, originally identified as PARK6. The causative gene was identified to code for a large multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). The combined genetic and biochemical evidence supports a hypothesis in which the LRRK2 kinase function is causally involved in the pathogenesis of sporadic and familial forms of PD, and therefore that LRRK2 kinase inhibitors could be useful for treatment. Although LRRK2 has so far not been crystallised, the use of homology modelling and crystallographic surrogates has allowed the optimisation of chemical structures such that compounds of high selectivity with good brain penetration and appropriate pharmacokinetic properties are now available for understanding the biology of LRRK2 in vitro and in vivo. This chapter reviews LRRK2 biology, the structural biology of LRRK2 and gives an overview of inhibitors of LRRK2.
连锁分析和全基因组关联研究已经在12号染色体上确定了一个迟发性帕金森病的遗传风险位点，最初被确定为PARK6。致病基因被确定为编码一种大型多功能蛋白，即富含亮氨酸重复激酶2（LRRK2）。综合的遗传和生化证据支持这样一种假说，即LRRK2激酶功能因果性地参与散发性和家族性帕金森病的发病机制，因此LRRK2激酶抑制剂可能对治疗有用。尽管到目前为止LRRK2尚未结晶，但同源建模和晶体学替代物的使用使得化学结构得以优化，从而现在有了具有高选择性、良好脑渗透性和适当药代动力学性质的化合物，可用于在体外和体内了解LRRK2的生物学特性。本章综述了LRRK2生物学、LRRK2的结构生物学，并概述了LRRK2抑制剂。
