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

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 phosp...

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Bibliographic Details
Published in:PloS one 2018-05, Vol.13 (5), p.e0196761
Main Authors: Walter, Anne, Chaikuad, Apirat, Helmer, Renate, Loaëc, Nadège, Preu, Lutz, Ott, Ingo, Knapp, Stefan, Meijer, Laurent, Kunick, Conrad
Format: Article
Language:English
Subjects:
Analysis
Biology and Life Sciences
Cancer
Cancer therapies
Cdc2 protein
Cell Line, Tumor
Chromatography
Consortia
Crystallization
Crystallography, X-Ray
Cyclin-Dependent Kinases - antagonists & inhibitors
Cyclin-Dependent Kinases - chemistry
Docking
Down syndrome
Drug Screening Assays, Antitumor
Funding
Genomics
Humans
Inhibitors
Kinases
Life sciences
Medicine and health sciences
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Open source software
Pharmaceuticals
Phosphorylation
Physical Sciences
Protein Binding
Protein Conformation
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein kinases
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - chemistry
Proteins
Research and Analysis Methods
RNA Splicing - drug effects
Selectivity
Serine
Splicing factors
Structure-Activity Relationship
Threonine
Tumor cell lines
Tyrosine
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Description
Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0196761