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

SUBMITTER: Kim H 

PROVIDER: S-EPMC5007978 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Kim Hyeongki H   Lee Kyu-Sun KS   Kim Ae-Kyeong AK   Choi Miri M   Choi Kwangman K   Kang Mingu M   Chi Seung-Wook SW   Lee Min-Sung MS   Lee Jeong-Soo JS   Lee So-Young SY   Song Woo-Joo WJ   Yu Kweon K   Cho Sungchan S  

Disease models & mechanisms 20160707 8


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  ...[more]

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