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- Title
Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype.
- Authors
Walter, Anne; Chaikuad, Apirat; Helmer, Renate; Loaëc, Nadège; Preu, Lutz; Ott, Ingo; Knapp, Stefan; Meijer, Laurent; Kunick, Conrad
- Abstract
Cdc2-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.
- Subjects
SERINE/THREONINE kinases; CANCER cells; GENETIC engineering; TISSUE scaffolds; MOLECULAR docking
- Publication
PLoS ONE, 2018, Vol 13, Issue 5, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0196761