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...
Main Authors: | , , , , , , , , |
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Format: | Journal article |
Language: | English |
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Public Library of Science
2018
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_version_ | 1797095648004145152 |
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author | Walter, A Chaikuad, A Helmer, R Loaëc, N Preu, L Ott, I Knapp, S Meijer, L Kunick, C |
author_facet | Walter, A Chaikuad, A Helmer, R Loaëc, N Preu, L Ott, I Knapp, S Meijer, L Kunick, C |
author_sort | Walter, A |
collection | OXFORD |
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. |
first_indexed | 2024-03-07T04:30:51Z |
format | Journal article |
id | oxford-uuid:ce42844c-98d0-4961-96f9-ee6118c6cee1 |
institution | University of Oxford |
language | English |
last_indexed | 2024-03-07T04:30:51Z |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | dspace |
spelling | oxford-uuid:ce42844c-98d0-4961-96f9-ee6118c6cee12022-03-27T07:34:33ZMolecular structures of cdc2-like kinases in complex with a new inhibitor chemotypeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ce42844c-98d0-4961-96f9-ee6118c6cee1EnglishSymplectic Elements at OxfordPublic Library of Science2018Walter, AChaikuad, AHelmer, RLoaëc, NPreu, LOtt, IKnapp, SMeijer, LKunick, CCdc2-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. |
spellingShingle | Walter, A Chaikuad, A Helmer, R Loaëc, N Preu, L Ott, I Knapp, S Meijer, L Kunick, C 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 |
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