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 |
| Published: |
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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