Chemical Genetic Transcriptional Fingerprinting for Selectivity Profiling of Kinase Inhibitors
| Autor: | Kevin S. Currie, J. Andrew Whitney, Julie DiPaolo, Tarif Awad, Shan Jiang, Dapeng Qian, Arun Ramamurthy, Mark Velleca, Johnny Peppers, Scott Alderucci, Xiaobing Qian |
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| Rok vydání: | 2007 |
| Předmět: |
Drug
media_common.quotation_subject Kidney Peptide Mapping Cell Line immune system diseases hemic and lymphatic diseases Drug Discovery medicine Functional selectivity Humans Bruton's tyrosine kinase Protein Kinase Inhibitors B cell Oligonucleotide Array Sequence Analysis media_common biology Kinase Gene Expression Profiling Gene expression profiling medicine.anatomical_structure Biochemistry biology.protein Molecular Medicine Biological Assay Protein Kinases Chemical genetics Tyrosine kinase Transcription Factors |
| Zdroj: | ASSAY and Drug Development Technologies. 5:49-64 |
| ISSN: | 1557-8127 1540-658X |
| DOI: | 10.1089/adt.2006.032 |
| Popis: | The importance of protein kinases as a major class of drug targets across multiple diseases has generated a critical need for technologies that enable the identification of potent and selective kinase inhibitors. Bruton's tyrosine kinase (Btk) is a compelling drug target in multiple therapeutic areas, including systemic lupus erythematosus, asthma, rheumatoid arthritis, and B cell malignancies. We have combined potent, selective kinase inhibition through chemical genetics with gene expression profiling to identify a "fingerprint" of transcriptional changes associated with selective Btk kinase inhibition. The Btk transcriptional fingerprint shows remarkable relevance for Btk's biological roles and was used for functional selectivity profiling of two kinase inhibitor compounds. The fingerprint was able to rank the compounds by relative selectivity for Btk, and revealed broader off-target effects than observed in a broad panel of biochemical kinase cross screens. In addition to being useful for functional selectivity profiling, the fingerprint genes are themselves potential preclinical and clinical biomarkers for developing Btk-directed therapies. |
| Databáze: | OpenAIRE |
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