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

• Main Authors: Anne Walter, Apirat Chaikuad, Renate Helmer, Nadège Loaëc, Lutz Preu, Ingo Ott, Stefan Knapp, Laurent Meijer, Conrad Kunick
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2018-01-01
• Series: PLoS ONE
• Online Access: http://europepmc.org/articles/PMC5933782?pdf=render

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.