Abstract：
The Pax family of developmental control genes are frequently deregulated in human disease. In the kidney, Pax2 is expressed in developing nephrons but not in adult proximal and distal tubules, whereas polycystic kidney epithelia or renal cell carcinoma continues to express high levels. Pax2 reduction in mice or cell culture can slow proliferation of cystic epithelial cells or renal cancer cells. Thus, inhibition of Pax activity may be a viable, cell-type-specific therapy. We designed an unbiased, cell-based, high-throughput screen that identified triazolo pyrimidine derivatives that attenuate Pax transactivation ability. We show that BG-1 inhibits Pax2-positive cancer cell growth and target gene expression but has little effect on Pax2-negative cells. Chromatin immunoprecipitation suggests that these inhibitors prevent Pax protein interactions with the histone H3K4 methylation complex at Pax target genes in renal cells. Thus, these compounds may provide structural scaffolds for kidney-specific inhibitors with therapeutic potential.
摘要：
发育控制基因的Pax家族在人类疾病中经常失调。在肾脏，Pax2在发育中的肾单位中表达，但在成人近端和远端小管中不表达，而多囊肾上皮或肾细胞癌持续表达高水平。小鼠或细胞培养物中的Pax2减少可以减缓囊性上皮细胞或肾癌细胞的增殖。因此，抑制Pax活性可能是可行的，细胞类型特异性治疗。我们设计了一个无偏见的，基于细胞，高通量筛选，鉴定出削弱Pax反式激活能力的三唑并嘧啶衍生物。我们显示BG-1抑制Pax2阳性癌细胞生长和靶基因表达，但对Pax2阴性细胞影响不大。染色质免疫沉淀表明，这些抑制剂可防止Pax蛋白与肾细胞中Pax靶基因处的组蛋白H3K4甲基化复合物相互作用。因此，这些化合物可以为具有治疗潜力的肾脏特异性抑制剂提供结构支架.
