title: 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.
authors.affiliation: Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28115, Republic of Korea Department of Biomolecular Science, University of Science and Technology, Daejeon 34113, Republic of Korea.
authors.forename: Hyeongki
authors.initials: H
authors.lastname: Kim
authors.affiliation: Neurophysiology Research Group, Hazard Monitoring BioNano Research Center, Korea Research Institute of Bioscience and Biotechnology, Deajeon 34141, Republic of Korea Department of Functional Genomics, University of Science and Technology, Daejeon 34113, Republic of Korea.
authors.forename: Kyu-Sun
authors.initials: KS
authors.lastname: Lee
authors.affiliation: Neurophysiology Research Group, Hazard Monitoring BioNano Research Center, Korea Research Institute of Bioscience and Biotechnology, Deajeon 34141, Republic of Korea.
authors.forename: Ae-Kyeong
authors.initials: AK
authors.lastname: Kim
authors.affiliation: Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28115, Republic of Korea.
authors.forename: Miri
authors.initials: M
authors.lastname: Choi
authors.affiliation: Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28115, Republic of Korea.
authors.forename: Kwangman
authors.initials: K
authors.lastname: Choi
authors.affiliation: Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28115, Republic of Korea.
authors.forename: Mingu
authors.initials: M
authors.lastname: Kang
authors.affiliation: Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
authors.forename: Seung-Wook
authors.initials: SW
authors.lastname: Chi
authors.affiliation: Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
authors.forename: Min-Sung
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Neurophysiology Research Group, Hazard Monitoring BioNano Research Center, Korea Research Institute of Bioscience and Biotechnology, Deajeon 34141, Republic of Korea Department of Functional Genomics, University of Science and Technology, Daejeon 34113, Republic of Korea.
authors.forename: Jeong-Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: International Cooperation Office, Ministry of Food & Drug Safety, Cheongju, Chungbuk 28159, Republic of Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Neurodegeneration Control Research Center, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea.
authors.forename: Woo-Joo
authors.initials: WJ
authors.lastname: Song
authors.affiliation: Neurophysiology Research Group, Hazard Monitoring BioNano Research Center, Korea Research Institute of Bioscience and Biotechnology, Deajeon 34141, Republic of Korea Department of Functional Genomics, University of Science and Technology, Daejeon 34113, Republic of Korea.
authors.forename: Kweon
authors.initials: K
authors.lastname: Yu
authors.affiliation: Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju, Chungbuk 28115, Republic of Korea Department of Biomolecular Science, University of Science and Technology, Daejeon 34113, Republic of Korea sungchan@kribb.re.kr.
authors.forename: Sungchan
authors.identifier: 0000-0001-7627-978X
authors.initials: S
authors.lastname: Cho
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000544:Alzheimer Disease / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D004331:Drosophila melanogaster / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D050778:NFATC Transcription Factors / Q000378:metabolism; D009287:Naphthyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010619:Phenazines; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D050778:NFATC Transcription Factors; D009287:Naphthyridines; D010619:Phenazines; D053764:Presenilin-1; D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D000255:Adenosine Triphosphate; C555142:silmitasertib; D017346:Protein Serine-Threonine Kinases; D019703:Calcineurin
keywords: Alzheimer's disease; CX-4945; DYRK1A; Down syndrome; Tau hyperphosphorylation