Azmi Asfar S, Bao Ginny W, Gao Jiankun, Mohammad Ramzi M, Sarkar Fazlul H
Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Curr Drug Discov Technol. 2013 Jun;10(2):147-54. doi: 10.2174/1570163811310020007.
Transcription factors (TFs) play central role in normal cellular physiology and their aberrant expression is linked to different diseases. Hepatocyte Nuclear Factors (HNFs) are TFs that have been recognized to play multiple roles in liver physiology. Emerging research has highlighted their function in the sustenance of solid tumors, indicating that HNFs could serve as possible therapeutic targets in cancer. Although, there have been many attempts to develop HNF targeted drugs, the myriad downstream targets associated with these transcription factors, some of which are critical for normal cell homeostasis, led to the realization that HNFs are not easily druggable. Therefore, identifying and optimizing drugs that can selectively inactivate HNFs is a challenge to the pharmaceutical industry. To achieve this, a more in-depth understanding is required of the HNFs binding partners, the protein interaction networks it regulates and the resulting phenotype. This calls for network analysis of the pathways regulated by HNFs and how chemical perturbations can selectively activate or suppress their functions. Network biology is an emerging field of research that is finding applications in cancer drug discovery. Specifically, network pharmacology is cementing its position in cancer research and has various applications such as biomarker identification, in determining synergistic drug pairs and in drug repurposing. Developing a network understanding of HNFs, the target it hits and responses thereof can enhance our ability to design drugs against these TFs. This article reviews how network pharmacology can help in the identification of druggable avenues in TFs and also allow the selection of drugs and their synergistic pairs against HNFs for cancer therapy.
转录因子（TFs）在正常细胞生理学中发挥着核心作用，其异常表达与多种疾病相关。肝细胞核因子（HNFs）是一类转录因子，已被证实在肝脏生理学中发挥多种作用。新兴研究突出了它们在实体瘤维持中的功能，表明HNFs可能成为癌症的潜在治疗靶点。尽管已经有许多开发针对HNFs药物的尝试，但与这些转录因子相关的众多下游靶点，其中一些对正常细胞稳态至关重要，这使得人们意识到HNFs不容易被药物作用。因此，识别和优化能够选择性使HNFs失活的药物对制药行业来说是一项挑战。要实现这一点，需要更深入地了解HNFs的结合伴侣、其调节的蛋白质相互作用网络以及由此产生的表型。这就需要对HNFs调节的信号通路以及化学扰动如何选择性激活或抑制其功能进行网络分析。网络生物学是一个新兴的研究领域，正在癌症药物研发中得到应用。具体而言，网络药理学在癌症研究中的地位日益巩固，具有多种应用，如生物标志物识别、确定协同药物对以及药物再利用。建立对HNFs及其作用靶点和相应反应的网络理解，可以增强我们设计针对这些转录因子药物的能力。本文综述了网络药理学如何有助于识别转录因子中的可药物作用途径，以及如何选择针对HNFs的药物及其协同药物对用于癌症治疗。
