Abstract
ABSTRACTDYRK1A is important in neuronal development and function, and its excessive activity is considered a significant pathogenic factor in Down syndrome and Alzheimer's disease. Thus, inhibition of DYRK1A has been suggested to be a new strategy to modify the disease. Very few compounds, however, have been reported to act as inhibitors, and their potential clinical uses require further evaluation. Here, we newly identify CX-4945, the safety of which has been already proven in the clinical setting, as a potent inhibitor of DYRK1A that acts in an ATP-competitive manner. The inhibitory potency of CX-4945 on DYRK1A (IC50=6.8 nM) in vitro was higher than that of harmine, INDY or proINDY, which are well-known potent inhibitors of DYRK1A. CX-4945 effectively reverses the aberrant phosphorylation of Tau, amyloid precursor protein (APP) and presenilin 1 (PS1) in mammalian cells. To our surprise, feeding with CX-4945 significantly restored the neurological and phenotypic defects induced by the overexpression of minibrain, an ortholog of human DYRK1A, in the Drosophila model. Moreover, oral administration of CX-4945 acutely suppressed Tau hyperphosphorylation in the hippocampus of DYRK1A-overexpressing mice. Our research results demonstrate that CX-4945 is a potent DYRK1A inhibitor and also suggest that it has therapeutic potential for DYRK1A-associated diseases.
Highlights
CX-4945 is a potent inhibitor of Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) we examined whether CX-4945 inhibits DYRK1A in mammalian cells
CX-4945 has a modulatory effect on Down syndrome (DS)- and Alzheimer’s disease (AD)-related calcineurin-NFAT signaling Because deregulation of calcineurin and nuclear factor of activated T cells (NFAT) signaling is related to the development of a DS- and AD-like phenotype, and because DYRK1A plays an important role in this signaling pathway (Arron et al, 2006), we examined the effect of CX-4945 on NFAT signaling involving DYRK1A by imaging the translocation of Flag-tagged NFATc1
We identified a novel inhibitor of DYRK1A, CX-4945, which showed stronger inhibitory activity than harmine, INDY and proINDY, which are well-known potent inhibitors of DYRK1A
Summary
DS is characterized by various symptoms, including mental retardation and congenital heart defects, as well as by defects in immune and endocrine systems (Becker and Joost, 1999). These featured phenotypes are closely associated with the overexpression or hyperactivity of many genes that can be mapped within the Down syndrome critical region (DSCR) on chromosome 21 (Guimera et al, 1999; Wiseman et al, 2009). Mice with lowered DYRK1A expression show phenotypic effects similar to those in mice overexpressing DYRK1A, indicating that DYRK1A activity is tightly controlled during normal brain development and that a dosage imbalance in DYRK1A expression affects brain structure and function (Arque et al, 2008; Benavides-Piccione et al, 2005; Fotaki et al, 2002, 2004)
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