A chemical with proven clinical safety restores Down syndrome-related phenotypes via DYRK1A inhibition

Abstract

DYRK1A 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.

X‐ray Structures and Feasibility Assessment of CLK2 Inhibitors for Phelan–McDermid Syndrome

“…Apart from our own focus on CLK2 as a molecular target for the treatment of autistic features in PMDS patients with SHANK3 deletions, various research groups have suggested functional modulation of the closely related kinase Dyrk1A as a potential therapeutic modality in addressing the cognitive and behavioral deficits in Down syndrome . We hope that this work may prove helpful in the development of ATP‐competitive Dyrk1A inhibitors, with the likely required selectivity over CLK1, ‐2, and ‐4, which are associated with adverse genotoxic potential.…”

“…Two publications on CX‐4945 by Kim et al. described this compound in its role as a highly potent CLK inhibitor, and in its role as a highly potent Dyrk1A inhibitor; Dyrk1A inhibition is proposed to be a potential treatment for Down syndrome . The high potency of CLK inhibitor Cpd‐2 is described by Araki et al .…”

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

“…In this regard, several new molecules that inhibit DYRK1A activity have been proven to reduce some AD phenotypes such as tau expression or phosphorylation, APP levels or Aβ load (Kim et al, 2016;Abbassy et al, 2015;Contadeur et al, 2015). Future studies should test the efficacy of the only DYRK1A inhibitor that has been so far tested in humans, epigallocatechin-gallate (EGCG) (De la Torre et al, 2014; to prevent different AD-associated alterations.…”

Dyrk1 inhibition improves Alzheimer's disease‐like pathology

“…In this proof‐of‐concept study, we report that Dyrk1 is a valid new target for AD treatment and show that its chronic inhibition reduced Aβ and tau pathology and ameliorated cognitive deficits in 3xTg‐AD mice. These data are consistent with previous results indicating that CX‐4945, a selective and potent Dyrk1a inhibitor, reduces tau pathology in multiple systems (Kim et al ., ). Taken together these results clearly indicate that Dyrk1 represents a valid therapeutic target for AD and support the development of new, effective, and clinically safe compounds aimed at reducing Dyrk1 activity.…”