Page 50 - I. Chemical biology and drug discovery

[I. Chemical biology and drug discovery-28]

A naturally-derived DYRK1A inhibitor rescues Down

syndrome-related phenotypes

Young-wook Ham¹˙²˙#, Miri Choi¹˙²˙#, Ae-kyeong Kim³, Joo-Youn Lee⁴, Jung-Nyoung Heo⁵, Min-Hyo Ki⁶,
Sang-Bae Han², Kyu-Sun Lee³, Sungchan Cho¹˙⁷˙*

¹Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Cheongju-si 28116,

Republic of Korea, ²College of Pharmacy, Chungbuk National University, Cheongju-si 28644, Republic of Korea,
³Bionanotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141,
Republic of Korea, ⁴Chemical Data-Driven Research Center, Korea Research Institute of Chemical Technology,

Daejeon 34114, Republic of Korea, ⁵Bioorganic Science Division, Korea Research Institute of Chemical Technology,

Daejeon 34122, Republic of Korea, ⁶Center Research Institute, Samjin Pharm. Co.,LTD , Seongnam-si 04054,
Republic of Korea, ⁷Department of Biomolecular Science, KRIBB School of Bioscience, Korea University of Science
and Technology, Daejeon 34113, Republic of Korea

DYRK1A is a significant pathogenic factor in Down syndrome (DS). Thus, inhibition of DYRK1A is considered as a
therapeutic strategy to modify the disease. Here, we identified Aristolactam BIII as a novel naturally-derived DYRK1A

inhibitor through two-step screening approach using structure-based virtual screening of >400,000 KCB chemical
library (1st step) and cell-based NFAT-RE promoter assay (2nd step). Aristolactam BIII potently inhibited the kinase

activity of DYRK1A in vitro (IC50 = 9.67 nM) and effectively suppressed DYRK1A-mediated hyperphosphorylation of
Tau and Presenilin 1 in mammalian cells, which was stronger than those of other DYRK1A inhibitors. Aristolactam

BIII rescued neurological and phenotypic defects of Down syndrome-like Drosophila model. Moreover, oral
administration of Aristolactam BIII acutely suppressed Tau hyperphosphorylation in the brain of DYRK1A TG mice.

In the open field test, Aristolactam BIII (1 mg/kg) significantly ameliorated the anxiety-like behavior of DYRK1A TG
mice. Together, our results obviously demonstrate that Aristolactam BIII as a novel DYRK1A inhibitor rescues Down
syndrome phenotypes in cells and in vivo and also suggest its therapeutic potential for the treatment of DYRK1A-

related diseases including DS and Alzheimer’s disease.