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Discovery of azabenzimidazole derivatives as potent, selective inhibitors of TBK1/IKKε kinases
- Source :
- Bioorganic & Medicinal Chemistry Letters. 22:2063-2069
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- The design, synthesis and biological evaluation of a series of azabenzimidazole derivatives as TBK1/IKKε kinase inhibitors are described. Starting from a lead compound 1a, iterative design and SAR exploitation of the scaffold led to analogues with nM enzyme potencies against TBK1/IKKε. These compounds also exhibited excellent cellular activity against TBK1. Further structure-based design to improve selectivity over CDK2 and Aurora B resulted in compounds such as 5b-e. These probe compounds will facilitate study of the complex cancer biology of TBK1 and IKKε.
- Subjects :
- Models, Molecular
Stereochemistry
Clinical Biochemistry
Aurora B kinase
Pharmaceutical Science
Protein Serine-Threonine Kinases
Biochemistry
Structure-Activity Relationship
chemistry.chemical_compound
TANK-binding kinase 1
Aurora Kinases
Neoplasms
Drug Discovery
Aurora Kinase B
Humans
Structure–activity relationship
skin and connective tissue diseases
Protein Kinase Inhibitors
Molecular Biology
chemistry.chemical_classification
Aza Compounds
biology
Chemistry
Kinase
Cyclin-Dependent Kinase 2
Organic Chemistry
Cyclin-dependent kinase 2
Combinatorial chemistry
I-kappa B Kinase
enzymes and coenzymes (carbohydrates)
HEK293 Cells
Enzyme
Drug Design
biology.protein
Molecular Medicine
Benzimidazoles
biological phenomena, cell phenomena, and immunity
Lead compound
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 22
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....850cfb76a6abe2e1ced95ab15332958c