Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer’s Disease

• Published in: Journal of medicinal chemistry 2024-05, Vol.67 (9), p.6922-6937
• Main Authors: Warren, Hunter T., Saeger, Hannah N., Tombari, Robert J., Chytil, Milan, Rasmussen, Kurt, Olson, David. E.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Animals; Drug Design; Dyrk Kinases; Humans; Mice; Phosphorylation; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; tau Proteins - antagonists & inhibitors; tau Proteins - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01696

Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer’s disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.