DYRK1A kinase inhibition with emphasis on neurodegeneration: A comprehensive evolution story-cum-perspective

• Published in: European journal of medicinal chemistry 2018-10, Vol.158, p.559-592
• Main Authors: Pathak, Ankita, Rohilla, Ankit, Gupta, Tanya, Akhtar, Md Jawaid, Haider, Md Rafi, Sharma, Kalicharan, Haider, Kashif, Yar, M. Shahar
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Amyloid precursor protein; Animals; Computer-Aided Design; Down Syndrome - drug therapy; Down Syndrome - metabolism; Down Syndrome - physiopathology; Down's syndrome critical region (DSCR) Alzheimer's disease; Drug Discovery - methods; Dyrk Kinases; DYRK1A; Humans; Molecular Targeted Therapy - methods; Neurodegeneration; Neurogenesis - drug effects; 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
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.08.093

Alzheimer, the fourth leading cause of death embodies a key responsible event including formation of β-amyloid protein clustering to amyloid plaque on blood vessels. The origin of above events is Amyloid precursor protein (APP) which is an integral membrane protein known for its function in synapses formation. Modern research had proposed that the over expression of DYRK1A (Dual specificity tyrosine phosphorylation regulated kinase1A, a family of protein kinases, positioned within the Down's syndrome critical region (DSCR) on human chromosome 21causes phosphorylation of APP protein resulting in its cleavage to Aβ 40, 42 and tau proteins (regulated by beta and gamma secretase) which plays critical role in early onset of Alzheimer's disease (AD) detected in Down's syndrome (DS), leading to permanent functional and structural deformities which results ultimately into neuro-degeneration and neuronal death. Therefore, DYRK1A emerges as a potential target for prevention of neuro-degeneration and hence Alzheimer. Presently, the treatment methods for Down's syndrome, as well as Alzheimer's disease are extremely biased and represent a major deficiency for therapeutic necessities. We hereby, focus our review on the current status of the research and contributions in the development of DYRK1A inhibitors. [Display omitted] •Alzheimer embodies several key responsible events like β-amyloid protein clustering to amyloid plaque and oxidative phosphorylation of ARAs.•In search of treatment, DYRK1A has been evaluated and targeted at almost every step from its maturation to its final expression.•Because of its involvement in numerous parallel signaling cascade, it is difficult to hamper off-target effects associated with its inhibition.•Conventional therapies including natural chemotherapeutic agents are still playing major role in providing potent cores for designing of new inhibitors.