Recent Advances in the Design, Synthesis, and Biological Evaluation of Selective DYRK1A Inhibitors: A New Avenue for a Disease Modifying Treatment of Alzheimer’s?

Abstract

With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health.

cdc-Like/Dual-Specificity Tyrosine Phosphorylation–Regulated Kinases Inhibitor Leucettine L41 Induces mTOR-Dependent Autophagy: Implication for Alzheimer’s Disease

“…SR proteins are phosphorylated by several protein kinases, including SR protein kinases (Gui et al, 1994) and the dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs; de Graaf et al, 2004) and cdc-like kinase 1 (CLK1; Duncan et al, 1997), the activity of which is required to maintain the phosphorylation state of SR proteins (Yomoda et al, 2008). Given the growing number of examples where splicing is abnormally regulated in human disease (review in Singh and Cooper, 2012), it is no surprise that there is increasing interest in pharmacological inhibitors of SR protein kinases, DYRKs, and CLKs as potential therapeutic drugs (review in Hagiwara, 2005;Smith et al, 2012). In this context we recently described leucettines, a family of low molecular weight inhibitors of DYRKs and CLKs derived from the marine natural product leucettamine B (Debdab et al, 2011;Tahtouh et al, 2012).…”

Pharmacology of Modulators of Alternative Splicing

“…This family phosphorylates proteins on serine, threonine, and tyrosine residues and is highly conserved across species, It shows very little homology with other kinases outside the catalytic domain (Smith et al, 2012). …”

“…Although the exact cellular functions of this kinase are still unknown, it is thought to play a critical role in the development of Down syndrome and Alzheimer’s disease. In fact, the DYRK1A gene is located within the Down syndrome critical region of chromosome 21, and increased activity of DYRK1A has been reported in various brain compartments in subjects that suffer from Down syndrome and other neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and Pick’s diseases (Tejedor and Hämmerle, 2011; Smith et al, 2012). …”

Prospective study directed to the synthesis of unsymmetrical linked bis-5-arylidene rhodanine derivatives via “one-pot two steps” reactions under microwave irradiation with their antitumor activity

“…diseases including Alzheimer's disease (AD), Down syndrome (Smith et al, 2012), and also cancer (Ionescu et al, 2012;Xiao et al, 2013;Ling et al, 2013). Encouraged by these preliminary results, we continued to explore the design and the synthesis of an expanded series of N,N'-bis-(5-arylidene-4-oxo-3,5-dihydro-4H-imidazol-2-yl)diamines as potential protein kinase inhibitors from appropriate symmetric alkyldiamines as flexible linkers (Coulibaly et al, 2012a).…”