Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype.

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ID: 22619
2018
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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.
Reference Key
walter2018molecularplos Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Walter, Anne;Chaikuad, Apirat;Helmer, Renate;Loaëc, Nadège;Preu, Lutz;Ott, Ingo;Knapp, Stefan;Meijer, Laurent;Kunick, Conrad;
Journal PloS one
Year 2018
DOI
10.1371/journal.pone.0196761
URL
Keywords Keywords not found

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