Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
Nat Chem. 2011 Aug 21;3(9):725-31. doi: 10.1038/nchem.1114.
Transcription factors are proteins that bind specifically to defined DNA sequences to promote gene expression. Targeting transcription factors with small molecules to modulate the expression of certain genes has been notoriously difficult to achieve. The natural product thiostrepton is known to reduce the transcriptional activity of FOXM1, a transcription factor involved in tumorigenesis and cancer progression. Herein we demonstrate that thiostrepton interacts directly with FOXM1 protein in the human breast cancer cells MCF-7. Biophysical analyses of the thiostrepton-FOXM1 interaction provide additional insights on the molecular mode of action of thiostrepton. In cellular experiments, we show that thiostrepton can inhibit the binding of FOXM1 to genomic target sites. These findings illustrate the potential druggability of transcription factors and provide a molecular basis for targeting the FOXM1 family with small molecules.
转录因子是能够特异性结合特定 DNA 序列以促进基因表达的蛋白质。利用小分子靶向转录因子来调节某些基因的表达一直是一项极具挑战性的任务。天然产物硫链丝菌素被认为可以降低参与肿瘤发生和癌症进展的转录因子 FOXM1 的转录活性。本文中，我们证明硫链丝菌素在人乳腺癌细胞 MCF-7 中直接与 FOXM1 蛋白相互作用。对硫链丝菌素-FOXM1 相互作用的生物物理分析提供了关于硫链丝菌素作用模式的更多见解。在细胞实验中，我们表明硫链丝菌素可以抑制 FOXM1 与基因组靶位点的结合。这些发现说明了转录因子的潜在成药性，并为利用小分子靶向 FOXM1 家族提供了分子基础。
