Targeting GRK2 and GRK5 for treating chronic degenerative diseases: Advances and future perspectives

Ya Zhang; Jifa Zhang; Jiaxing Wang; Hao Chen; Liang Ouyang; Yuxi Wang

doi:10.1016/j.ejmech.2022.114668

Targeting GRK2 and GRK5 for treating chronic degenerative diseases: Advances and future perspectives

Eur J Med Chem. 2022 Dec 5:243:114668. doi: 10.1016/j.ejmech.2022.114668. Epub 2022 Aug 13.

Authors

Ya Zhang¹, Jifa Zhang², Jiaxing Wang³, Hao Chen³, Liang Ouyang⁴, Yuxi Wang⁵

Affiliations

¹ Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; College of Life Sciences, Sichuan University, Chengdu, 610064, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
² Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
³ Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, 38163, Tennessee, United States.
⁴ Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: ouyangliang@scu.edu.cn.
⁵ Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Research Institution of Altitude Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Research Center, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: yuxiwang@scu.edu.cn.

PMID: 36055000
DOI: 10.1016/j.ejmech.2022.114668

Abstract

The development of small-molecule inhibitors targeting G protein-coupled receptor kinase 2 (GRK2) and G protein-coupled receptor kinase 5 (GRK5) for the treatment of chronic degenerative diseases has attracted wide attention. GRK2 and GRK5 can regulate essential physiological processes by phosphorylating G protein-coupled receptor (GPCR). Alterations in the functional levels of GRK2 and GRK5 have been found in a variety of chronic degenerative diseases, such as cardiovascular diseases, neurodegenerative diseases, cancers, type 2 diabetes, and rheumatoid arthritis (RA). Abnormal GRK2 and GRK5 expression contribute to the development of chronic degenerative diseases through environmental molecular mechanisms, making them promising molecular targets for treating chronic degenerative diseases. To date, many novel GRK2 and GRK5 inhibitors have been reported for the treatment of chronic degenerative diseases. We focus on the recent progress of single and dual-target inhibitors of GRK2/GRK5. This review summarizes the structural optimization rationale, structure-activity relationships (SARs), and the latest application in the treatment of chronic degenerative diseases. We believe it will shed light on the future development of small molecule inhibitors of GRK2 and GRK5, as well as the clinical applications in chronic degenerative diseases.

Keywords: Chronic degenerative diseases; Dual-target inhibitors; GRK2; GRK5; Structure-activity relationship.

Publication types

Review

MeSH terms

Cardiovascular Diseases*
Diabetes Mellitus, Type 2*
G-Protein-Coupled Receptor Kinase 2 / metabolism
G-Protein-Coupled Receptor Kinase 5 / metabolism
Humans
Neurodegenerative Diseases* / drug therapy
Structure-Activity Relationship

Substances

G-Protein-Coupled Receptor Kinase 2
GRK5 protein, human
G-Protein-Coupled Receptor Kinase 5