GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

Abstract

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood–brain barrier (BBB) permeability and drug-like properties.

Unveiling the Multitarget Anti-Alzheimer Drug Discovery Landscape: A Bibliometric Analysis

“…Deregulation of kinases, such as GSK-3β, FYN kinase, and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), seems to be directly linked to several neurodegenerative diseases. Thus, these kinases, which are interconnected with different signaling pathways, are considered to play a key role in the neurokinome so that they may constitute emerging targets for future multitarget compounds [ 55 ]. Rho kinases (ROCKs) are the main effectors of RhoA, a member of the Rho family of GTPases that has important roles in synaptic processes.…”

“…In microglia and astrocytes, p38α regulates brain inflammation and it is a critical contributor to the toxicity of Aβ, tau, and inflammation to synapses, whereas p38α deficiency or inhibition is beneficial in AD animal models [ 84 , 85 ]. Thus, we suggest that p38α is considered a promising central node to be hit in combination with other kinases involved in tau pathology, such as GSK-3β, CDK5, CK1/2, DYRK1A and FYN, with prominent roles in tau phosphorylation [ 55 , 86 ].…”

The Omnipresence of DYRK1A in Human Diseases

“…In addition to neurological disorders, DYRK1A dysregulation has been linked to cancer (especially lung and pancreatic cancers), glioblastoma, melanoma, leukemia, diabetes, and heart diseases [ 78 , 110 , 111 ]. Consequently, individuals with DS are at increased risk for developing multiple congenital disorders [ 24 ].…”

Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins

“…For example, amantadine, originally approved as a drug against Asian influenza, combines dopaminergic and glutamatergic properties and is effective in the symptomatic treatment of PD [97]. Protein kinases, such as GSK-3, Fyn, and DYRK1A, are central to neurodegenerative diseases because of their regulatory roles in different signal transduction cascades; multi-target inhibitors of such kinases prevented neurotoxin-induced cell death in in vitro PD models (for references see [98]). Analysis of disease-related genes and PPI networks may help in the development of potential drugs, as shown for AD [99].…”