Small-molecule LRRK2 inhibitors for PD therapy: Current achievements and future perspectives

Jiarui Hu; Dan Zhang; Keyue Tian; Changyu Ren; Heng Li; Congcong Lin; Xiaoli Huang; Jie Liu; Wuyu Mao; Jifa Zhang

doi:10.1016/j.ejmech.2023.115475

Small-molecule LRRK2 inhibitors for PD therapy: Current achievements and future perspectives

Eur J Med Chem. 2023 Aug 5:256:115475. doi: 10.1016/j.ejmech.2023.115475. Epub 2023 May 10.

Authors

Jiarui Hu¹, Dan Zhang¹, Keyue Tian², Changyu Ren³, Heng Li³, Congcong Lin⁴, Xiaoli Huang⁵, Jie Liu⁶, Wuyu Mao⁷, Jifa Zhang⁸

Affiliations

¹ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
² State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
³ Chengdu Fifth People's Hospital, Chengdu, 611130, Sichuan, China.
⁴ Department of Medicinal Chemistry and Natural Medicine Chemistry, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
⁵ Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China.
⁶ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: liujie2011@scu.edu.cn.
⁷ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Center of Gerontology and Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: wuyanmao1@sina.com.
⁸ Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy and Joint Research Institution of Altitude Health and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: zjf298257@163.com.

PMID: 37201428
DOI: 10.1016/j.ejmech.2023.115475

Abstract

Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein that orchestrates a diverse array of cellular processes, including vesicle transport, autophagy, lysosome degradation, neurotransmission, and mitochondrial activity. Hyperactivation of LRRK2 triggers vesicle transport dysfunction, neuroinflammation, accumulation of α-synuclein, mitochondrial dysfunction, and the loss of cilia, ultimately leading to Parkinson's disease (PD). Therefore, targeting LRRK2 protein is a promising therapeutic strategy for PD. The clinical translation of LRRK2 inhibitors was historically impeded by issues surrounding tissue specificity. Recent studies have identified LRRK2 inhibitors that have no effect on peripheral tissues. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides a summary of the structure and biological functions of LRRK2, along with an overview of the binding modes and structure-activity relationships (SARs) of small-molecule inhibitors targeting LRRK2. It offers valuable references for developing novel drugs targeting LRRK2.

Keywords: Binding mode; Kinase inhibitor; LRRK2; Parkinson's disease; Structure-activity relationship.

Publication types

Review

MeSH terms

Autophagy
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
Lysosomes / metabolism
Parkinson Disease* / drug therapy
Parkinson Disease* / metabolism
Synaptic Transmission

Substances

Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
LRRK2 protein, human