A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease

Publication type:
Journal article
Metadata:
Autoren
  • Trevor Dale
  • Paul A Clarke
  • Christina Esdar
  • Dennis Waalboer
  • Olajumoke Adeniji-Popoola
  • Maria-Jesus Ortiz-Ruiz
  • Aurelie Mallinger
  • Rahul S Samant
  • Paul Czodrowski
  • Djordje Musil
  • Daniel Schwarz
  • Klaus Schneider
  • Mark Stubbs
  • Ken Ewan
  • Elizabeth Fraser
  • Robert TePoele
  • Will Court
  • Gary Box
  • Melanie Valenti
  • Alexis de Haven Brandon
  • Sharon Gowan
  • Felix Rohdich
  • Florence Raynaud
  • Richard Schneider
  • Oliver Poeschke
  • Andree Blaukat
  • Paul Workman
  • Kai Schiemann
  • Suzanne A Eccles
  • Dirk Wienke
  • Julian Blagg
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000365834000017&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1038/nchembio.1952
eISSN
1552-4469
Externe Identifier
  • Clarivate Analytics Document Solution ID: CX6TG
  • PubMed Identifier: 26502155
ISSN
1552-4450
Ausgabe der Veröffentlichung
12
Zeitschrift
NATURE CHEMICAL BIOLOGY
Paginierung
973 - 980
Datum der Veröffentlichung
2015
Status
Published
Titel
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease
Sub types
  • Article
Ausgabe der Zeitschrift
11

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Trevor Dale
  • Paul A Clarke
  • Christina Esdar
  • Dennis Waalboer
  • Olajumoke Adeniji-Popoola
  • Maria-Jesus Ortiz-Ruiz
  • Aurélie Mallinger
  • Rahul S Samant
  • Paul Czodrowski
  • Djordje Musil
  • Daniel Schwarz
  • Klaus Schneider
  • Mark Stubbs
  • Ken Ewan
  • Elizabeth Fraser
  • Robert TePoele
  • Will Court
  • Gary Box
  • Melanie Valenti
  • Alexis de Haven Brandon
  • Sharon Gowan
  • Felix Rohdich
  • Florence Raynaud
  • Richard Schneider
  • Oliver Poeschke
  • Andree Blaukat
  • Paul Workman
  • Kai Schiemann
  • Suzanne A Eccles
  • Dirk Wienke
  • Julian Blagg
DOI
10.1038/nchembio.1952
eISSN
1552-4469
ISSN
1552-4450
Ausgabe der Veröffentlichung
12
Zeitschrift
Nature Chemical Biology
Sprache
en
Online publication date
2015
Paginierung
973 - 980
Datum der Veröffentlichung
2015
Status
Published
Herausgeber
Springer Science and Business Media LLC
Herausgeber URL
http://dx.doi.org/10.1038/nchembio.1952
Datum der Datenerfassung
2023
Titel
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease
Ausgabe der Zeitschrift
11

Data source: Crossref

Abstract
There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.
Addresses
  • School of Bioscience, Cardiff University, Cardiff, UK.
Autoren
  • Trevor Dale
  • Paul A Clarke
  • Christina Esdar
  • Dennis Waalboer
  • Olajumoke Adeniji-Popoola
  • Maria-Jesus Ortiz-Ruiz
  • Aurélie Mallinger
  • Rahul S Samant
  • Paul Czodrowski
  • Djordje Musil
  • Daniel Schwarz
  • Klaus Schneider
  • Mark Stubbs
  • Ken Ewan
  • Elizabeth Fraser
  • Robert TePoele
  • Will Court
  • Gary Box
  • Melanie Valenti
  • Alexis de Haven Brandon
  • Sharon Gowan
  • Felix Rohdich
  • Florence Raynaud
  • Richard Schneider
  • Oliver Poeschke
  • Andree Blaukat
  • Paul Workman
  • Kai Schiemann
  • Suzanne A Eccles
  • Dirk Wienke
  • Julian Blagg
DOI
10.1038/nchembio.1952
eISSN
1552-4469
Externe Identifier
  • PubMed Identifier: 26502155
  • PubMed Central ID: PMC4677459
Funding acknowledgements
  • Cancer Research UK: 15937
  • Cancer Research UK: C368/A6743
  • Cancer Research UK: 11566
  • Cancer Research UK: C309/A11566
  • Cancer Research UK: A368/A7990
  • Biotechnology and Biological Sciences Research Council: BB/D00117X/1
  • Cancer Research UK: A11566
Open access
true
ISSN
1552-4450
Ausgabe der Veröffentlichung
12
Zeitschrift
Nature chemical biology
Schlüsselwörter
  • Cell Line, Tumor
  • Humans
  • Colonic Neoplasms
  • Pyridines
  • Spiro Compounds
  • Cyclin-Dependent Kinases
  • Protein Kinase Inhibitors
  • Molecular Probes
  • Molecular Structure
  • Models, Molecular
  • Cyclin-Dependent Kinase 8
Sprache
eng
Medium
Print-Electronic
Online publication date
2015
Open access status
Open Access
Paginierung
973 - 980
Datum der Veröffentlichung
2015
Status
Published
Datum der Datenerfassung
2015
Titel
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.
Sub types
  • Research Support, Non-U.S. Gov't
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
11

Files

https://europepmc.org/articles/pmc4677459?pdf=render

Data source: Europe PubMed Central

Abstract
There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.
Date of acceptance
2015
Autoren
  • Trevor Dale
  • Paul A Clarke
  • Christina Esdar
  • Dennis Waalboer
  • Olajumoke Adeniji-Popoola
  • Maria-Jesus Ortiz-Ruiz
  • Aurélie Mallinger
  • Rahul S Samant
  • Paul Czodrowski
  • Djordje Musil
  • Daniel Schwarz
  • Klaus Schneider
  • Mark Stubbs
  • Ken Ewan
  • Elizabeth Fraser
  • Robert TePoele
  • Will Court
  • Gary Box
  • Melanie Valenti
  • Alexis de Haven Brandon
  • Sharon Gowan
  • Felix Rohdich
  • Florence Raynaud
  • Richard Schneider
  • Oliver Poeschke
  • Andree Blaukat
  • Paul Workman
  • Kai Schiemann
  • Suzanne A Eccles
  • Dirk Wienke
  • Julian Blagg
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/26502155
DOI
10.1038/nchembio.1952
eISSN
1552-4469
Externe Identifier
  • NIH Manuscript Submission ID: EMS65392
  • PubMed Central ID: PMC4677459
Funding acknowledgements
  • Cancer Research UK: C309/A11566
  • Cancer Research UK: A368/A7990
  • Biotechnology and Biological Sciences Research Council: BB/D00117X/1
  • Cancer Research UK: C368/A6743
  • Cancer Research UK: 11566
  • Cancer Research UK: A11566
  • Cancer Research UK: 15937
Ausgabe der Veröffentlichung
12
Zeitschrift
Nat Chem Biol
Schlüsselwörter
  • Cell Line, Tumor
  • Colonic Neoplasms
  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases
  • Humans
  • Models, Molecular
  • Molecular Probes
  • Molecular Structure
  • Protein Kinase Inhibitors
  • Pyridines
  • Spiro Compounds
Sprache
eng
Country
United States
Paginierung
973 - 980
Datum der Veröffentlichung
2015
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2016
Titel
A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.
Sub types
  • Journal Article
  • Research Support, Non-U.S. Gov't
Ausgabe der Zeitschrift
11

Data source: PubMed

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