Department of Pathology, University of Michigan, BSRB 2049, 109 Zina Pitcher Drive, Ann Arbor, MI 48109, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
Department of Pathology, University of Michigan, BSRB 2049, 109 Zina Pitcher Drive, Ann Arbor, MI 48109, USA.
Cell Chem Biol. 2022 Mar 17;29(3):412-422.e4. doi: 10.1016/j.chembiol.2021.11.003. Epub 2021 Nov 24.
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.
Pax 家族的发育控制基因在人类疾病中经常失调。在肾脏中，Pax2 在发育中的肾单位中表达，但不在成年近端和远端小管中表达，而多囊肾病上皮或肾细胞癌仍持续高水平表达。在小鼠或细胞培养中减少 Pax2 可以减缓囊性上皮细胞或肾癌细胞的增殖。因此，抑制 Pax 活性可能是一种可行的、细胞类型特异性的治疗方法。我们设计了一种无偏倚的、基于细胞的高通量筛选方法，该方法可以识别出三唑嘧啶衍生物，这些衍生物可以减弱 Pax 的转录激活能力。我们表明，BG-1 抑制 Pax2 阳性癌细胞的生长和靶基因表达，但对 Pax2 阴性细胞几乎没有影响。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 靶基因的组蛋白 H3K4 甲基化复合物相互作用。因此，这些化合物可能为具有治疗潜力的肾脏特异性抑制剂提供结构支架。
