Targeting leucine-rich repeat kinase 2 (LRRK2) for the treatment of Parkinson's disease

被引：19

作者：

Domingos, Sofia ^{[1
]}

Duarte, Teresa ^{[2
]}

Saraiva, Lucilia ^{[3
]}

Guedes, Rita C. ^{[1
]}

Moreira, Rui ^{[1
]}

机构：

[1] Univ Lisbon, Fac Farm, Res Inst Med iMed ULisboa, Ave Prof Gama Pinto, P-1649003 Lisbon, Portugal

[2] Univ Lisbon, Inst Super Tecn, CQE, Ave Rovisco Pais, P-1049001 Lisbon, Portugal

[3] Univ Porto, Fac Farm, Dept Ciencias Biol, LAQV REQUIMTE,Lab Microbiol, Rua Jorge Viterbo Ferreira 228, P-4050313 Porto, Portugal

来源：

FUTURE MEDICINAL CHEMISTRY | 2019年 / 11卷 / 15期

关键词：

blood-brain barrier; kinase inhibitors; kinase selectivity; LRRK2; LRRK2 G2019S mutation; inhibitors; neurodegeneration; Parkinson's disease; serine-threonine kinase; small molecule inhibitors; AUTOSOMAL-DOMINANT PARKINSONISM; BRAIN-PENETRANT; HIGHLY POTENT; INHIBITORS; DISCOVERY; MUTATION; GENE; BINDING; DESIGN; IDENTIFICATION;

D O I：

10.4155/fmc-2018-0484

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Leucine-rich repeat kinase 2 (LRRK2) is a serine-threonine kinase involved in multiple cellular processes and signaling pathways. LRRK2 mutations are associated with autosomal-inherited Parkinson's disease (PD), and evidence suggests that LRRK2 pathogenic variants generally increase kinase activity. Therefore, inhibition of LRRK2 kinase function is a promising therapeutic strategy for PD treatment. The search for drug-like molecules capable of reducing LRRK2 kinase activity in PD led to the design of selective LRRK2 inhibitors predicted to be within the CNS drug-like space. This review highlights the journey that translates chemical tools for interrogating the role of LRRK2 in PD into promising drug candidates, addressing the challenges in discovering selective and brain-penetrant LRRK2 modulators and exploring the structure-activity relationship of distinct LRRK2 inhibitors.

引用

页码：1953 / 1977

页数：25

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