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Title 

A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition

 

CX-4945의 DYRK1A 억제를 통한 다운증후군 결함 개선

Authors 

Hyeongki KimKyu-Sun LeeAe Kyung KimMiri ChoiKwangman ChoiMingu KangSeung-Wook ChiMin-Sung LeeJeong Soo LeeS Y LeeW J SongKweon YuSungchan Cho

Publisher 

Company of Biologists

Issue Date 

2016

Citation 

Disease Models and Mechanisms, vol. 9, no. 7, pp. 839-848

Keywords 

Alzheimer's diseaseCX-4945Down syndromeDYRK1ATau hyperphosphorylation

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 ofDYRK1A 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) inmammalian cells. To our surprise, feedingwith 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.

ISSN 

1754-8403

Link 

http://dx.doi.org/10.1242/dmm.025668

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2019-05-02


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