Discovery of potent and selective CDK8 inhibitors from an HSP90 pharmacophore

[Display omitted] 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 wer...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2016-03, Vol.26 (5), p.1443-1451
Main Authors: Schiemann, Kai, Mallinger, Aurélie, Wienke, Dirk, Esdar, Christina, Poeschke, Oliver, Busch, Michael, Rohdich, Felix, Eccles, Suzanne A., Schneider, Richard, Raynaud, Florence I., Czodrowski, Paul, Musil, Djordje, Schwarz, Daniel, Urbahns, Klaus, Blagg, Julian
Format: Article
Language:English
Subjects:
Animals
CDK19
CDK8
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - metabolism
Crystallography, X-Ray
Cyclin-Dependent Kinase 8 - antagonists & inhibitors
Cyclin-Dependent Kinase 8 - metabolism
Dose-Response Relationship, Drug
Drug Discovery
HSP90
HSP90 Heat-Shock Proteins - metabolism
Humans
Indazoles
Indazoles - administration & dosage
Indazoles - chemistry
Indazoles - pharmacology
Mediator complex
Mice
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Rats
Structure-Activity Relationship
Substrate Specificity
WNT pathway inhibitors
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Summary:[Display omitted] 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2016.01.062