HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.
HNF4α antagonists discovered by a high-throughput screen for modulators of the human insulin promoter.
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DOI：
10.1016/j.chembiol.2012.05.014
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发表时间：
2012-07-27
影响因子：
--
通讯作者：
Levine F
中科院分区：
文献类型：
--
作者：
Kiselyuk A;Lee SH;Farber-Katz S;Zhang M;Athavankar S;Cohen T;Pinkerton AB;Ye M;Bushway P;Richardson AD;Hostetler HA;Rodriguez-Lee M;Huang L;Spangler B;Smith L;Higginbotham J;Cashman J;Freeze H;Itkin-Ansari P;Dawson MI;Schroeder F;Cang Y;Mercola M;Levine F
肝细胞核因子 (HNF)4α 是细胞类型基因表达的中央调节因子，在代谢稳态中发挥关键作用，包括肝细胞、肠上皮细胞和胰腺 β 细胞。尽管脂肪酸被发现占据 HNF4α 配体结合袋并被提议充当配体，但关于 HNF4α 配体的性质以及结合的生理作用仍存在争议。在此，我们报告通过高通量筛选人胰岛素启动子效应子发现了有效的合成 HNF4α 拮抗剂。这些分子以高亲和力与 HNF4α 结合，并调节已知 HNF4α 靶基因的表达。值得注意的是，它们被发现在体外和体内对癌细胞系具有选择性细胞毒性，尽管体内效力受到次优药代动力学特性的限制。 HNF4α 生物活性调节剂的发现提出了一种可能性，即涉及 HNF4α 的疾病，例如糖尿病和癌症，可能适合通过调节 HNF4α 活性进行药物干预。
Hepatocyte Nuclear Factor (HNF)4α is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic β-cells. Although fatty acids were found to occupy the HNF4α ligand-binding pocket and proposed to act as ligands, there is controversy about both the nature of HNF4α ligands as well as the physiological role of the binding. Here, we report the discovery of potent synthetic HNF4α antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4α with high affinity and modulated the expression of known HNF4α target genes. Notably, they were found to be selectively cytotoxic to cancer cell lines in vitro and in vivo, although in vivo potency was limited by suboptimal pharmacokinetic properties. The discovery of bioactive modulators for HNF4α raises the possibility that diseases involving HNF4α, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4α activity.
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