Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Aurelie Mallinger
- Kai Schiemann
- Christian Rink
- Frank Stieber
- Michel Calderini
- Simon Crumpler
- Mark Stubbs
- Olajumoke Adeniji-Popoola
- Oliver Poeschke
- Michael Busch
- Paul Czodrowski
- Djordje Musil
- Daniel Schwarz
- Maria-Jesus Ortiz-Ruiz
- Richard Schneider
- Ching Thai
- Melanie Valenti
- Alexis de Haven Brandon
- Rosemary Burke
- Paul Workman
- Trevor Dale
- Dirk Wienke
- Paul A Clarke
- Christina Esdar
- Florence I Raynaud
- Suzanne A Eccles
- Felix Rohdich
- Julian Blagg
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000370212700020&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1021/acs.jmedchem.5b01685
- eISSN
- 1520-4804
- Externe Identifier
- Clarivate Analytics Document Solution ID: DD8YL
- PubMed Identifier: 26796641
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 3
- Zeitschrift
- JOURNAL OF MEDICINAL CHEMISTRY
- Paginierung
- 1078 - 1101
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Titel
- Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19
- Sub types
- Article
- Ausgabe der Zeitschrift
- 59
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Aurélie Mallinger
- Kai Schiemann
- Christian Rink
- Frank Stieber
- Michel Calderini
- Simon Crumpler
- Mark Stubbs
- Olajumoke Adeniji-Popoola
- Oliver Poeschke
- Michael Busch
- Paul Czodrowski
- Djordje Musil
- Daniel Schwarz
- Maria-Jesus Ortiz-Ruiz
- Richard Schneider
- Ching Thai
- Melanie Valenti
- Alexis de Haven Brandon
- Rosemary Burke
- Paul Workman
- Trevor Dale
- Dirk Wienke
- Paul A Clarke
- Christina Esdar
- Florence I Raynaud
- Suzanne A Eccles
- Felix Rohdich
- Julian Blagg
- DOI
- 10.1021/acs.jmedchem.5b01685
- eISSN
- 1520-4804
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 3
- Zeitschrift
- Journal of Medicinal Chemistry
- Sprache
- en
- Online publication date
- 2016
- Paginierung
- 1078 - 1101
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Herausgeber
- American Chemical Society (ACS)
- Herausgeber URL
- http://dx.doi.org/10.1021/acs.jmedchem.5b01685
- Datum der Datenerfassung
- 2023
- Titel
- Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19
- Ausgabe der Zeitschrift
- 59
Data source: Crossref
- Abstract
- The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.
- Addresses
- Cancer Research UK Cancer Therapeutics Unit at The Institute of Cancer Research, London, SW7 3RP, U.K.
- Autoren
- Aurélie Mallinger
- Kai Schiemann
- Christian Rink
- Frank Stieber
- Michel Calderini
- Simon Crumpler
- Mark Stubbs
- Olajumoke Adeniji-Popoola
- Oliver Poeschke
- Michael Busch
- Paul Czodrowski
- Djordje Musil
- Daniel Schwarz
- Maria-Jesus Ortiz-Ruiz
- Richard Schneider
- Ching Thai
- Melanie Valenti
- Alexis de Haven Brandon
- Rosemary Burke
- Paul Workman
- Trevor Dale
- Dirk Wienke
- Paul A Clarke
- Christina Esdar
- Florence I Raynaud
- Suzanne A Eccles
- Felix Rohdich
- Julian Blagg
- DOI
- 10.1021/acs.jmedchem.5b01685
- eISSN
- 1520-4804
- Externe Identifier
- PubMed Identifier: 26796641
- PubMed Central ID: PMC5362750
- Funding acknowledgements
- Cancer Research UK: 11566
- Cancer Research UK: C309/A11566
- Royal Marsden NHS Foundation Trust:
- Open access
- true
- ISSN
- 0022-2623
- Ausgabe der Veröffentlichung
- 3
- Zeitschrift
- Journal of medicinal chemistry
- Schlüsselwörter
- Caco-2 Cells
- Animals
- Dogs
- Humans
- Mice
- Rats
- Rats, Wistar
- Neoplasms, Experimental
- Aminopyridines
- Cyclin-Dependent Kinases
- Administration, Oral
- Xenograft Model Antitumor Assays
- Molecular Structure
- Structure-Activity Relationship
- Biological Availability
- Dose-Response Relationship, Drug
- Solubility
- Models, Molecular
- Female
- Male
- Small Molecule Libraries
- Drug Discovery
- Cyclin-Dependent Kinase 8
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2016
- Open access status
- Open Access
- Paginierung
- 1078 - 1101
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Datum der Datenerfassung
- 2016
- Titel
- Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
- Sub types
- Research Support, Non-U.S. Gov't
- research-article
- Journal Article
- Ausgabe der Zeitschrift
- 59
Files
https://europepmc.org/articles/PMC5362750?pdf=render
Data source: Europe PubMed Central
- Abstract
- The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.
- Autoren
- Aurélie Mallinger
- Kai Schiemann
- Christian Rink
- Frank Stieber
- Michel Calderini
- Simon Crumpler
- Mark Stubbs
- Olajumoke Adeniji-Popoola
- Oliver Poeschke
- Michael Busch
- Paul Czodrowski
- Djordje Musil
- Daniel Schwarz
- Maria-Jesus Ortiz-Ruiz
- Richard Schneider
- Ching Thai
- Melanie Valenti
- Alexis de Haven Brandon
- Rosemary Burke
- Paul Workman
- Trevor Dale
- Dirk Wienke
- Paul A Clarke
- Christina Esdar
- Florence I Raynaud
- Suzanne A Eccles
- Felix Rohdich
- Julian Blagg
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/26796641
- DOI
- 10.1021/acs.jmedchem.5b01685
- eISSN
- 1520-4804
- Externe Identifier
- PubMed Central ID: PMC5362750
- Funding acknowledgements
- Cancer Research UK: 11566
- Cancer Research UK: C309/A11566
- Ausgabe der Veröffentlichung
- 3
- Zeitschrift
- J Med Chem
- Schlüsselwörter
- Administration, Oral
- Aminopyridines
- Animals
- Biological Availability
- Caco-2 Cells
- Cyclin-Dependent Kinase 8
- Cyclin-Dependent Kinases
- Dogs
- Dose-Response Relationship, Drug
- Drug Discovery
- Female
- Humans
- Male
- Mice
- Models, Molecular
- Molecular Structure
- Neoplasms, Experimental
- Rats
- Rats, Wistar
- Small Molecule Libraries
- Solubility
- Structure-Activity Relationship
- Xenograft Model Antitumor Assays
- Sprache
- eng
- Country
- United States
- Paginierung
- 1078 - 1101
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2016
- Titel
- Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
- Sub types
- Journal Article
- Research Support, Non-U.S. Gov't
- Ausgabe der Zeitschrift
- 59
Data source: PubMed
- Beziehungen:
-