DYRK1A inhibitors for disease therapy: Current status and perspectives

Tong Liu; Yuxi Wang; Jiaxing Wang; Changyu Ren; Hao Chen; Jifa Zhang

doi:10.1016/j.ejmech.2021.114062

DYRK1A inhibitors for disease therapy: Current status and perspectives

Eur J Med Chem. 2022 Feb 5:229:114062. doi: 10.1016/j.ejmech.2021.114062. Epub 2021 Dec 21.

Authors

Tong Liu¹, Yuxi Wang², Jiaxing Wang³, Changyu Ren⁴, Hao Chen³, Jifa Zhang⁵

Affiliations

¹ Targeted Tracer Research and development laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Institute for 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, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, 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 Institute for 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, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, 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 Department of Pharmacy, Chengdu Fifth People's Hospital, Chengdu, Sichuan, 611130, China.
⁵ Targeted Tracer Research and development laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, Joint Institute for 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, Department of Respiratory and Critical Care Medicine, National Clinical Research Center for Geriatrics, 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: zjf298257@163.com.

PMID: 34954592
DOI: 10.1016/j.ejmech.2021.114062

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A) is a conserved protein kinase that plays essential roles in various biological processes. It is located in the region q22.2 of chromosome 21, which is involved in the pathogenesis of Down syndrome (DS). Moreover, DYRK1A has been shown to promote the accumulation of amyloid beta (Aβ) peptides leading to gradual Tau hyperphosphorylation, which contributes to neurodegeneration. Additionally, alterations in the DRK1A expression are also associated with cancer and diabetes. Recent years have witnessed an explosive increase in the development of DYRK1A inhibitors. A variety of novel DYRK1A inhibitors have been reported as potential treatments for human diseases. In this review, the latest therapeutic potential of DYRK1A for different diseases and the novel DYRK1A inhibitors discoveries are summarized, guiding future inhibitor development and structural optimization.

Keywords: Cancer; DS; DYRK1A; DYRK1A inhibitor; Drug design; Structure activity relationships.

Publication types

Review

MeSH terms

Amyloid beta-Peptides / metabolism
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Drug Design
Dyrk Kinases
Gene Expression Regulation / drug effects
Humans
Hypoglycemic Agents / chemistry*
Hypoglycemic Agents / pharmacology
Neuroprotective Agents / chemistry*
Neuroprotective Agents / pharmacology
Phosphorylation
Protein Binding
Protein Conformation
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacology
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / genetics
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / genetics
Signal Transduction
Structure-Activity Relationship

Substances

Amyloid beta-Peptides
Antineoplastic Agents
Hypoglycemic Agents
Neuroprotective Agents
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases