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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933782/ https://www.ncbi.nlm.nih.gov/pubmed/29723265 http://dx.doi.org/10.1371/journal.pone.0196761 |
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author | Walter, Anne Chaikuad, Apirat Helmer, Renate Loaëc, Nadège Preu, Lutz Ott, Ingo Knapp, Stefan Meijer, Laurent Kunick, Conrad |
author_facet | Walter, Anne Chaikuad, Apirat Helmer, Renate Loaëc, Nadège Preu, Lutz Ott, Ingo Knapp, Stefan Meijer, Laurent Kunick, Conrad |
author_sort | Walter, Anne |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5933782 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-59337822018-05-18 Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype Walter, Anne Chaikuad, Apirat Helmer, Renate Loaëc, Nadège Preu, Lutz Ott, Ingo Knapp, Stefan Meijer, Laurent Kunick, Conrad PLoS One Research Article 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. Public Library of Science 2018-05-03 /pmc/articles/PMC5933782/ /pubmed/29723265 http://dx.doi.org/10.1371/journal.pone.0196761 Text en © 2018 Walter et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Walter, Anne Chaikuad, Apirat Helmer, Renate Loaëc, Nadège Preu, Lutz Ott, Ingo Knapp, Stefan Meijer, Laurent Kunick, Conrad Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype |
title | Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype |
title_full | Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype |
title_fullStr | Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype |
title_full_unstemmed | Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype |
title_short | Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype |
title_sort | molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933782/ https://www.ncbi.nlm.nih.gov/pubmed/29723265 http://dx.doi.org/10.1371/journal.pone.0196761 |
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