6ft8
Crystal structure of CLK1 in complex with inhibitor 8gCrystal structure of CLK1 in complex with inhibitor 8g
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 PubMedCdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies. Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype.,Walter A, Chaikuad A, Helmer R, Loaec N, Preu L, Ott I, Knapp S, Meijer L, Kunick C PLoS One. 2018 May 3;13(5):e0196761. doi: 10.1371/journal.pone.0196761., eCollection 2018. PMID:29723265[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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