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

DOI: 10.1371/journal.pone.0196761 DOI Help

Authors: Anne Walter (Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig) , Apirat Chaikuad (Structural Genomics Consortium, Oxford University) , Renate Helmer (Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig) , Nadège Loaëc (ManRos Therapeutics) , Lutz Preu (Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig) , Ingo Ott (Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig) , Stefan Knapp (Structural Genomics Consortium, University of Oxford) , Laurent Meijer (ManRos Therapeutics) , Conrad Kunick (Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Plos One , VOL 13

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 8421

Open Access Open Access

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.

Journal Keywords: Chlorides; Crystal structure; Hydrogen bonding; Indoles; CNS melanoma; Kinase inhibitors; High performance liquid chromatography; Binding analysis

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

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