Library-based discovery of DYRK1A/CLK1 inhibitors from natural product extracts.
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.
Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland.
Patrick
P
Grabher
Emilie
E
Durieu
Eirini
E
Kouloura
Maria
M
Halabalaki
Leandros A
LA
Skaltsounis
Laurent
L
Meijer
Matthias
M
Hamburger
Olivier
O
Potterat
D000818:Animals; D002366:Cassia / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D034182:Cuscuta / Q000737:chemistry; D004642:Emodin / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D004789:Enzyme Activation; D005419:Flavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005658:Fungi / Q000737:chemistry; D006247:Harmine / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D032442:Larrea / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D032443:Peganum / Q000737:chemistry; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018515:Plant Leaves / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012639:Seeds / Q000737:chemistry; D000097603:Dyrk Kinases
D004642:Emodin; D005419:Flavonoids; D006247:Harmine; D010936:Plant Extracts; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C487687:ombuine; C066780:Clk dual-specificity kinases