Small-Molecule Inhibitors of the SOX18 Transcription Factor
Small-Molecule Inhibitors of the SOX18 Transcription Factor
复制标题
SOX18 转录因子的小分子抑制剂
DOI：
10.1016/j.chembiol.2017.01.003
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发表时间：
2017-03-16
影响因子：
8.6
通讯作者：
Francois, Mathias
中科院分区：
文献类型：
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作者：
Fontaine, Frank;Overman, Jeroen;Francois, Mathias
在过去的40年里，转录因子(TF)的药理学调节只取得了很小的成功。这主要是由于以阻断蛋白质/DNA结合或干扰翻译后修饰为中心的标准药物发现方法。转铁蛋白生物学领域的最新进展揭示了蛋白质-蛋白质相互作用在其作用模式中的核心作用。为了调节SOX18 Tf的活性，SOX18 Tf是一种已知的血管发育和疾病生长调节因子，我们筛选了一个海洋提取物文库，以寻找潜在的小分子抑制剂。我们鉴定了两个化合物，它们激发了一系列合成的SOX18抑制剂，能够干扰SOX18 HMG DNA结合域，并破坏依赖HMG的蛋白质与RBPJ的相互作用。这些化合物还干扰了基于细胞的报告基因系统中SOX18的转录活性。这种方法可能有助于开发一类新的基于抑制转铁蛋白活性的抗血管生成化合物。
Pharmacological modulation of transcription factors (TFs) has only met little success over the past four decades. This is mostly due to standard drug discovery approaches centered on blocking protein/DNA binding or interfering with post-translational modifications. Recent advances in the field of TF biology have revealed a central role of protein-protein interaction in their mode of action. In an attempt to modulate the activity of SOX18 TF, a known regulator of vascular growth in development and disease, we screened a marine extract library for potential small-molecule inhibitors. We identified two compounds, which inspired a series of synthetic SOX18 inhibitors, able to interfere with the SOX18 HMG DNA-binding domain, and to disrupt HMG-dependent protein-protein interaction with RBPJ. These compounds also perturbed SOX18 transcriptional activity in a cell-based reporter gene system. This approach may prove useful in developing a new class of anti-angiogenic compounds based on the inhibition of TF activity.