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 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.
Metadaten
Author:Anne Walter, Apirat ChaikuadORCiD, Renate Helmer, Nadège Loaëc, Lutz Preu, Ingo Ott, Stefan Knapp, Laurent Meijer, Conrad Kunick
URN:urn:nbn:de:hebis:30:3-465577
DOI:https://doi.org/10.1371/journal.pone.0196761
ISSN:1932-6203
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/29723265
Parent Title (English):PLoS One
Publisher:PLoS
Place of publication:Lawrence, Kan.
Contributor(s):Alessio Lodola
Document Type:Article
Language:English
Year of Completion:2018
Date of first Publication:2018/05/03
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2018/05/24
Tag:Binding analysis; CNS melanoma; Chlorides; Crystal structure; High performance liquid chromatography; Hydrogen bonding; Indoles; Kinase inhibitors
Volume:13
Issue:(5): e0196761
Page Number:29
First Page:1
Last Page:29
Note:
Copyright: © 2018 Walter et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
HeBIS-PPN:433858737
Institutes:Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0