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

PLoS One. 2018 May 3;13(5):e0196761. doi: 10.1371/journal.pone.0196761. eCollection 2018.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / chemistry
  • Drug Screening Assays, Antitumor
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Protein Conformation
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • RNA Splicing / drug effects
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Protein Serine-Threonine Kinases
  • Cyclin-Dependent Kinases