| Structural highlights
Function
[CLK1_HUMAN] Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates. Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA.[1] [2]
Publication Abstract from PubMed
The design and synthesis of new pyrido[3,4-g]quinazoline derivatives is described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A). The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/DYRK1A activity was validated by nanomolar potencies (compounds 12 and 13). CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket.
Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co-crystal structure.,Esvan YJ, Zeinyeh W, Boibessot T, Nauton L, Thery V, Knapp S, Chaikuad A, Loaec N, Meijer L, Anizon F, Giraud F, Moreau P Eur J Med Chem. 2016 Apr 5;118:170-177. doi: 10.1016/j.ejmech.2016.04.004. PMID:27128181[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Moeslein FM, Myers MP, Landreth GE. The CLK family kinases, CLK1 and CLK2, phosphorylate and activate the tyrosine phosphatase, PTP-1B. J Biol Chem. 1999 Sep 17;274(38):26697-704. PMID:10480872
- ↑ Eisenreich A, Bogdanov VY, Zakrzewicz A, Pries A, Antoniak S, Poller W, Schultheiss HP, Rauch U. Cdc2-like kinases and DNA topoisomerase I regulate alternative splicing of tissue factor in human endothelial cells. Circ Res. 2009 Mar 13;104(5):589-99. doi: 10.1161/CIRCRESAHA.108.183905. Epub, 2009 Jan 22. PMID:19168442 doi:10.1161/CIRCRESAHA.108.183905
- ↑ Esvan YJ, Zeinyeh W, Boibessot T, Nauton L, Thery V, Knapp S, Chaikuad A, Loaec N, Meijer L, Anizon F, Giraud F, Moreau P. Discovery of pyrido[3,4-g]quinazoline derivatives as CMGC family protein kinase inhibitors: Design, synthesis, inhibitory potency and X-ray co-crystal structure. Eur J Med Chem. 2016 Apr 5;118:170-177. doi: 10.1016/j.ejmech.2016.04.004. PMID:27128181 doi:https://dx.doi.org/10.1016/j.ejmech.2016.04.004
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