Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore
- Publication type:
- Journal article
- Metadata:
-
- Autoren
- Kai Schiemann
- Aurelie Mallinger
- Dirk Wienke
- Christina Esdar
- Oliver Poeschke
- Michael Busch
- Felix Rohdich
- Suzanne A Eccles
- Richard Schneider
- Florence I Raynaud
- Paul Czodrowski
- Djordje Musil
- Daniel Schwarz
- Klaus Urbahns
- Julian Blagg
- Autoren-URL
- https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000369941600016&DestLinkType=FullRecord&DestApp=WOS_CPL
- DOI
- 10.1016/j.bmcl.2016.01.062
- eISSN
- 1464-3405
- Externe Identifier
- Clarivate Analytics Document Solution ID: DD5DA
- PubMed Identifier: 26852363
- ISSN
- 0960-894X
- Ausgabe der Veröffentlichung
- 5
- Zeitschrift
- BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
- Schlüsselwörter
- WNT pathway inhibitors
- Mediator complex
- CDK8
- CDK19
- HSP90
- Indazoles
- Paginierung
- 1443 - 1451
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Titel
- Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore
- Sub types
- Article
- Ausgabe der Zeitschrift
- 26
Data source: Web of Science (Lite)
- Other metadata sources:
-
- Autoren
- Kai Schiemann
- Aurélie Mallinger
- Dirk Wienke
- Christina Esdar
- Oliver Poeschke
- Michael Busch
- Felix Rohdich
- Suzanne A Eccles
- Richard Schneider
- Florence I Raynaud
- Paul Czodrowski
- Djordje Musil
- Daniel Schwarz
- Klaus Urbahns
- Julian Blagg
- DOI
- 10.1016/j.bmcl.2016.01.062
- ISSN
- 0960-894X
- Ausgabe der Veröffentlichung
- 5
- Zeitschrift
- Bioorganic & Medicinal Chemistry Letters
- Sprache
- en
- Paginierung
- 1443 - 1451
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Herausgeber
- Elsevier BV
- Herausgeber URL
- http://dx.doi.org/10.1016/j.bmcl.2016.01.062
- Datum der Datenerfassung
- 2018
- Titel
- Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore
- Ausgabe der Zeitschrift
- 26
Data source: Crossref
- Abstract
- Here we describe the discovery and optimization of 3-benzylindazoles as potent and selective inhibitors of CDK8, also modulating CDK19, discovered from a high-throughput screening (HTS) campaign sampling the Merck compound collection. The primary hits with strong HSP90 affinity were subsequently optimized to potent and selective CDK8 inhibitors which demonstrate inhibition of WNT pathway activity in cell-based assays. X-ray crystallographic data demonstrated that 3-benzylindazoles occupy the ATP binding site of CDK8 and adopt a Type I binding mode. Medicinal chemistry optimization successfully led to improved potency, physicochemical properties and oral pharmacokinetics. Modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8, was demonstrated in an APC-mutant SW620 human colorectal carcinoma xenograft model following oral administration.
- Addresses
- Merck KGaA, 64293 Darmstadt, Germany. Electronic address: kai.schiemann@merckgroup.com.
- Autoren
- Kai Schiemann
- Aurélie Mallinger
- Dirk Wienke
- Christina Esdar
- Oliver Poeschke
- Michael Busch
- Felix Rohdich
- Suzanne A Eccles
- Richard Schneider
- Florence I Raynaud
- Paul Czodrowski
- Djordje Musil
- Daniel Schwarz
- Klaus Urbahns
- Julian Blagg
- DOI
- 10.1016/j.bmcl.2016.01.062
- eISSN
- 1464-3405
- Externe Identifier
- PubMed Identifier: 26852363
- Funding acknowledgements
- Cancer Research UK: 11566
- Cancer Research UK: C309/A11566
- Cancer Research UK:
- The Royal Marsden Hospital, London:
- The Institute of Cancer Research:
- Open access
- false
- ISSN
- 0960-894X
- Ausgabe der Veröffentlichung
- 5
- Zeitschrift
- Bioorganic & medicinal chemistry letters
- Schlüsselwörter
- Animals
- Humans
- Mice
- Rats
- Colorectal Neoplasms
- Indazoles
- Protein Kinase Inhibitors
- Crystallography, X-Ray
- Molecular Structure
- Structure-Activity Relationship
- Substrate Specificity
- Dose-Response Relationship, Drug
- Models, Molecular
- HSP90 Heat-Shock Proteins
- Drug Discovery
- Cyclin-Dependent Kinase 8
- Sprache
- eng
- Medium
- Print-Electronic
- Online publication date
- 2016
- Paginierung
- 1443 - 1451
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Datum der Datenerfassung
- 2016
- Titel
- Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 26
Data source: Europe PubMed Central
- Abstract
- Here we describe the discovery and optimization of 3-benzylindazoles as potent and selective inhibitors of CDK8, also modulating CDK19, discovered from a high-throughput screening (HTS) campaign sampling the Merck compound collection. The primary hits with strong HSP90 affinity were subsequently optimized to potent and selective CDK8 inhibitors which demonstrate inhibition of WNT pathway activity in cell-based assays. X-ray crystallographic data demonstrated that 3-benzylindazoles occupy the ATP binding site of CDK8 and adopt a Type I binding mode. Medicinal chemistry optimization successfully led to improved potency, physicochemical properties and oral pharmacokinetics. Modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8, was demonstrated in an APC-mutant SW620 human colorectal carcinoma xenograft model following oral administration.
- Date of acceptance
- 2016
- Autoren
- Kai Schiemann
- Aurélie Mallinger
- Dirk Wienke
- Christina Esdar
- Oliver Poeschke
- Michael Busch
- Felix Rohdich
- Suzanne A Eccles
- Richard Schneider
- Florence I Raynaud
- Paul Czodrowski
- Djordje Musil
- Daniel Schwarz
- Klaus Urbahns
- Julian Blagg
- Autoren-URL
- https://www.ncbi.nlm.nih.gov/pubmed/26852363
- DOI
- 10.1016/j.bmcl.2016.01.062
- eISSN
- 1464-3405
- Funding acknowledgements
- Cancer Research UK: 11566
- Cancer Research UK: C309/A11566
- Ausgabe der Veröffentlichung
- 5
- Zeitschrift
- Bioorg Med Chem Lett
- Schlüsselwörter
- CDK19
- CDK8
- HSP90
- Indazoles
- Mediator complex
- WNT pathway inhibitors
- Animals
- Colorectal Neoplasms
- Crystallography, X-Ray
- Cyclin-Dependent Kinase 8
- Dose-Response Relationship, Drug
- Drug Discovery
- HSP90 Heat-Shock Proteins
- Humans
- Indazoles
- Mice
- Models, Molecular
- Molecular Structure
- Protein Kinase Inhibitors
- Rats
- Structure-Activity Relationship
- Substrate Specificity
- Sprache
- eng
- Country
- England
- Paginierung
- 1443 - 1451
- PII
- S0960-894X(16)30060-9
- Datum der Veröffentlichung
- 2016
- Status
- Published
- Datum, an dem der Datensatz öffentlich gemacht wurde
- 2016
- Titel
- Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore.
- Sub types
- Journal Article
- Ausgabe der Zeitschrift
- 26
Data source: PubMed
- Beziehungen:
-