Chemical genetic transcriptional fingerprinting for selectivity profiling of kinase inhibitors.
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.
Jiang
Shan
S
CGI Pharmaceuticals, Inc., Branford, CT 06405, USA.
DiPaolo
Julie
J
Currie
Kevin
K
Alderucci
Scott
S
Ramamurthy
Arun
A
Peppers
Johnny
J
Qian
Xiaobing
X
Qian
Dapeng
D
Awad
Tarif
T
Velleca
Mark
M
Whitney
J Andrew
JA
D001681:Biological Assay / Q000379:methods; D002460:Cell Line; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010449:Peptide Mapping / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000032:analysis*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D011494:Protein Kinases