Identification and analysis of a selective DYRK1A inhibitor

• Published in: Biomedicine & pharmacotherapy Vol. 146; p. 112580
• Main Authors: Lin, Tony Eight, Chao, Min-Wu, HuangFu, Wei-Chun, Tu, Huang-Ju, Peng, Zhao-Xiang, Su, Chih-Jou, Sung, Tzu-Ying, Hsieh, Jui-Hua, Lee, Cheng-Chung, Yang, Chia-Ron, Pan, Shiow-Lin, Hsu, Kai-Cheng
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01.02.2022; Elsevier
• Subjects: Alzheimer’s disease; Cell Line; Dyrk Kinases; DYRK1A; Kinase inhibitor; Pharmacological interactions; Phosphorylation; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - antagonists & inhibitors; Small-molecule inhibitor; Structure-Activity Relationship; Structure-based virtual screening; tau Proteins - drug effects; Tubulin - drug effects; DYRK1A; Alzheimer’s disease; Structure-based virtual screening; Kinase inhibitor; Small-molecule inhibitor; Pharmacological interactions
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2021.112580

The dysregulation of DYRK1A is implicated in many diseases such as cancer, diabetes, and neurodegenerative diseases. Alzheimer’s disease is one of the most common neurodegenerative disease and has elevated interest in DYRK1A research. Overexpression of DYRK1A has been linked to the formation of tau aggregates. Currently, an effective therapeutic treatment that targets DYRK1A is lacking. A specific small-molecule inhibitor would further our understanding of the physiological role of DYRK1A in neurodegenerative diseases and could be presented as a possible therapeutic option. In this study, we identified pharmacological interactions within the DYRK1A active site and performed a structure-based virtual screening approach to identify a selective small-molecule inhibitor. Several compounds were selected in silico for enzymatic and cellular assays, yielding a novel inhibitor. A structure-activity relationship analysis was performed to identify areas of interactions for the compounds selected in this study. When tested in vitro, reduction of DYRK1A dependent phosphorylation of tau was observed for active compounds. The active compounds also improved tau turbidity, suggesting that these compounds could alleviate aberrant tau aggregation. Testing the active compound against a panel of kinases across the kinome revealed greater selectivity towards DYRK1A. Our study demonstrates a serviceable protocol that identified a novel and selective DYRK1A inhibitor with potential for further study in tau-related pathologies. [Display omitted] •A DYRK1A inhibitor was identified using a structure-based virtual screening protocol.•Comparing its analogs identified another potent hit.•In vitro assays show modulation to DYRK1A activity.•The identified compounds stabilize tubulin polymerization.•The identified inhibitors has potential use for probing neurodegenerative diseases.