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.
Anne Walter  1  2 ,  Apirat Chaikuad  3  4 ,  Renate Helmer  1 ,  Nadège Loaëc  5 ,  Lutz Preu  1 ,  Ingo Ott  1  2 ,  Stefan Knapp  3  4 ,  Laurent Meijer  5 ,  Conrad Kunick  1  2
Affiliations
  • 1. Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Braunschweig, Germany.
  • 2. Center of Pharmaceutical Engeneering (PVZ), Technische Universität Braunschweig, Braunschweig, Germany.
  • 3. Structural Genomics Consortium, Nuffield Department of Medicine, Oxford University, Oxford, United Kingdom.
  • 4. Institute for Pharmaceutical Chemistry, Structural Genomics Consortium and Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
  • 5. ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, Roscoff, France.
PMID: 29723265 DOI: 10.1371/journal.pone.0196761
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.

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