Abstract
The dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A possesses diverse
roles in neuronal development and adult brain physiology, and increased activity has
been linked to neurodegenerative diseases. Very few inhibitors of this kinase have
been reported up to now. Screening of a library of > 900 plant and fungal extracts
afforded 25 extracts with IC50s < 10 µg/mL against DYRK1A. To identify the active constituents, the extracts were
submitted to a process integrating physicochemical data with biological information,
referred to as HPLC-based activity profiling. Follow-up investigation of four extracts
led to the targeted isolation of harmine (1, IC50 0.022 µM) from Peganum harmala, emodin (3, IC50 4.2 µM) from Cassia nigricans, kaempferol (4, IC50 0.91 µM) from Cuscuta chinensis, and 3,8-di-O-methylherbacetin (11, IC50 8.6 µM), 3,3′,4′-tri-O-methylmyricetin (12, IC50 7.1 µM) and ombuin (15, IC50 1.7 µM) from Larrea tridentata as the active constituents. Active extracts and compounds were also tested on the
closely related cdc2-like kinase CLK1. Finally, the selectivity profile of compounds
was evaluated by including other members of the DYRKs and CLKs families. While the
flavonoids and emodin did not show significant differences in the potency of their
activities, harmine (1) was most active against DYRK1A, CLK1, and CLK4, and less potent against the other
kinases, with selectivity ranging from 2- to 20-fold.
Key words
library-based natural product screening - DYRK1A - CLK1 - HPLC-based activity profiling
- harmine - emodin - flavonoids -
Peganum harmala
- Zygophyllaceae -
Cuscuta chinensis
- Convolvulaceae -
Larrea tridentate
- Zygophyllaceae -
Cassia nigricans
- Caesalpiniaceae
