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

2016; The Company of Biologists; Linguagem: Inglês

10.1242/dmm.025668

1754-8411

Hyeongki Kim, Kyu‐Sun Lee, Ae‐Kyeong Kim, Miri Choi, Kwangman Choi, Min-Gu Kang, Seung‐Wook Chi, Min‐Sung Lee, Jeong-Soo Lee, Soyoung Lee, Woo‐Joo Song, Kweon Yu, Sungchan Cho,

Down syndrome and intellectual disability research

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 those of harmine, INDY, and proINDY, which are the 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 its therapeutic potential for DYRK1A-associated diseases.