6ft8

Publication Abstract from PubMed

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.

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.