A chemical with proven clinical safety rescues Down-syndrome-related phenotypes in through DYRK1A inhibition = CX-4945의 DYRK1A 억제를 통한 다운증후군 결함 개선

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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
Author(s)
Hyeongki Kim; Kyu-Sun LeeAe Kyung Kim; Miri Choi; Kwangman Choi; Mingu Kang; Seung-Wook Chi; Min-Sung Lee; Jeong Soo Lee; S Y Lee; W J Song; Kweon YuSungchan Cho
Bibliographic Citation
Disease Models & Mechanisms, vol. 9, no. 7, pp. 839-848
Publication Year
2016
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.
Keyword
Alzheimer's diseaseCX-4945Down syndromeDYRK1ATau hyperphosphorylation
ISSN
1754-8403
Publisher
Company Biologists Ltd
DOI
http://dx.doi.org/10.1242/dmm.025668
Type
Article
Appears in Collections:
Division of Research on National Challenges > Bionanotechnology Research Center > 1. Journal Articles
Division of Biomedical Research > 1. Journal Articles
Division of Biomedical Research > Microbiome Convergence Research Center > 1. Journal Articles
Ochang Branch Institute > Division of National Bio-Infrastructure > 1. Journal Articles
Ochang Branch Institute > Nucleic Acid Therapeutics Research Center > 1. Journal Articles
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