Jiang Shan, DiPaolo Julie, Currie Kevin, Alderucci Scott, Ramamurthy Arun, Peppers Johnny, Qian Xiaobing, Qian Dapeng, Awad Tarif, Velleca Mark, Whitney J Andrew
CGI Pharmaceuticals, Inc., Branford, CT 06405, USA.
Assay Drug Dev Technol. 2007 Feb;5(1):49-64. doi: 10.1089/adt.2006.032.
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.
蛋白质激酶作为针对多种疾病的一类主要药物靶点，其重要性引发了对能够鉴定强效和选择性激酶抑制剂的技术的迫切需求。布鲁顿酪氨酸激酶（Btk）在多个治疗领域都是引人注目的药物靶点，包括系统性红斑狼疮、哮喘、类风湿性关节炎和B细胞恶性肿瘤。我们通过化学遗传学实现强效、选择性激酶抑制，并结合基因表达谱分析，以鉴定与选择性Btk激酶抑制相关的转录变化“指纹”。Btk转录指纹显示出与Btk生物学作用的显著相关性，并用于两种激酶抑制剂化合物的功能选择性分析。该指纹能够根据对Btk的相对选择性对化合物进行排名，并揭示出比在广泛的生化激酶交叉筛选中观察到的更广泛的脱靶效应。除了用于功能选择性分析外，指纹基因本身还是开发Btk导向疗法的潜在临床前和临床生物标志物。
