Library-based Discovery of DYRK1A/CLK1 Inhibitors from Natural Product Extracts

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.

Pharmacophore and 3D-QSAR Characterization of 6-Arylquinazolin-4-amines as Cdc2-like Kinase 4 (Clk4) and Dual Specificity Tyrosine-phosphorylation-regulated Kinase 1A (Dyrk1A) Inhibitors

“…Some compounds have been identified as both Clk and Dyrk inhibitors, such as, 6-arylquinazolin-4-amine analogs, 5,12,13 leucettines, 14 bauerine C derivatives, 15 a benzothiazole analog, 16 and natural product extracts. 2 However, development of potent and selective Clk and Dyrk inhibitors is still yet to be explored. 12,13 …”

Natural Products as Potential Human Ether-A-Go-Go-Related Gene Channel Inhibitors – Screening of Plant-Derived Alkaloids

“…Given the structural diversity of the alkaloids included in this study, deriving structural features critical for hERG inhibition was not possible. However, it seems that alkaloids with an aporphine (17)(18)(19)(20) or benzophenanthridine (21)(22)(23)(24) scaffold are particularly prone to hERG block.…”

Medicinal uses, pharmacology, and phytochemistry of Convolvulaceae plants with central nervous system efficacies: A systematic review

“…Sivaraman et al () also revealed that kaempferol ( 20 ) has a good binding affinity with the target AChE enzyme, suggesting an anti‐AD effect. By screening of a library of more than 900 plant and fungal extracts, kaempferol ( 20 ) from C. chinensis showed a significant inhibitory effect in tyrosine‐phosphorylation‐regulated kinase DYRK1A with an IC 50 value of 0.91 μM, which will help neuronal development and adult brain physiology (Grabher et al, ).…”