Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.
Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice.
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转录因子 SOX18 的药理学靶向可延缓小鼠乳腺癌的发生
DOI：
10.7554/elife.21221
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发表时间：
2017-01-31
期刊：
影响因子：
7.7
通讯作者：
Francois M
中科院分区：
文献类型：
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作者：
Overman J;Fontaine F;Moustaqil M;Mittal D;Sierecki E;Sacilotto N;Zuegg J;Robertson AAB;Holmes K;Salim AA;Mamidyala S;Butler MS;Robinson AS;Lesieur E;Johnston W;Alexandrov K;Black BL;Hogan BM;De Val S;Capon RJ;Carroll JS;Bailey TL;Koopman P;Jauch R;Cooper MA;Gambin Y;Francois M
转录因子的药理学靶向为新疗法的开发带来了巨大希望，但基于阻断 DNA 结合、核穿梭或个体蛋白质伴侣招募的策略迄今为止取得的成功有限。转录因子通常参与复杂的相互作用网络，可能掩盖了特异性抑制单一蛋白质-蛋白质相互作用的效果。在这里，我们结合使用基因组学、蛋白质组学和生物物理学方法来发现一系列涉及 SOX18 转录因子的蛋白质-蛋白质相互作用，SOX18 转录因子是血管发育和疾病的已知调节因子。我们描述了一种小分子，它能够破坏 SOX18 依赖性相互作用的离散子集。该化合物在体外选择性抑制 SOX18 转录输出，并干扰斑马鱼幼虫的血管发育。在小鼠乳腺癌临床前模型中，使用这种抑制剂治疗可通过降低肿瘤血管密度和转移扩散来显着提高生存率。我们的研究验证了基于相互作用组的分子策略来干扰转录因子活性，以开发新的疾病疗法。
Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.