Small Molecule Inhibitors of the Transcriptional Activators ESX and NF-kB

描述（由申请人提供）：调节基因表达对细胞的正常生长和发育至关重要。控制这一复杂过程的神经网络的破坏与一系列人类癌症有关。这些疾病的核心通常是转录激活因子的功能失调，这些蛋白质与特定基因相关，并使它们启动，从而产生它们编码的蛋白质。这代表了通过识别直接抑制与乳腺癌相关的转录激活因子功能的分子来开发解决转录失调的治疗方法的机会。两种互补的方法将用于鉴定抑制两种转录激活因子ESX和NF- kappaB （p50/p65异源二聚体）功能的小分子（药物样），这两种转录激活因子与大约30%的乳腺癌有关。通过体外和体内研究的结合，这些分子将被单独或联合评估在阻断ErbB2（Her2）阳性乳腺癌生长和转移方面的有效性，并提供对其作用机制的详细了解。从更广泛的角度来看，本研究中发现的转录抑制剂将成为剖析转录失调与乳腺癌之间关系的杰出工具。我们对这些分子的研究也将用于建立一个有效的转录抑制剂应该表现出什么样的特征（效力、功效、特异性）的概况。通过这种方式，这里鉴定的分子将成为转录靶向治疗的原型，为未来的治疗研究开辟了新的途径。

DESCRIPTION (provided by applicant): Regulated gene expression is essential to the normal growth and development of cells. The disruption in the network that controls this complex process is correlated with a range of human cancers. Often at the heart of these diseases are malfunctioning transcriptional activators, proteins that associate with specific genes and turn them on such that the proteins they encode are produced. This represents an opportunity to develop therapies that address transcriptional misregulation by identifying molecules that directly inhibit the function of transcriptional activators associated with breast cancer. Two complementary approaches will be used to identify small (drug-like) molecules that inhibit the function of two transcriptional activators, ESX and NF- kappaB (p50/p65 heterodimer) implicated in approximately 30% of breast cancers. Through a combination of in vitro and in vivo studies, these molecules will be assessed as individually and in combination for effectiveness in blocking growth and metastasis of ErbB2(Her2)-positive breast cancer and to provide a detailed understanding of their mechanism of action. From a broader perspective, the transcriptional inhibitors identified in this study will be outstanding tools for dissecting the relationship between misregulated transcription and breast cancer. Our study of these molecules will also be used to build a profile of what characteristics (potency, efficacy, specificity) of an effective transcriptional inhibitor should exhibit. In this way, the molecules identified here will be prototype transcription- targeted therapeutics, opening new avenues for future therapeutic investigations. PUBLIC HEALTH RELEVANCE: Outlined in this proposal are two complementary approaches to identify small (drug-like) molecules that inhibit the function of two transcriptional activators implicated in approximately 30% of breast cancers. These molecules will be studied in several in vitro and in vivo models of breast cancer in order to evaluate their effectiveness at selectively halting the growth of the cancers associated with the transcriptional activators and to provide a detailed understanding of their mechanism of action. The molecules identified here will be prototype transcription-targeted therapeutics, opening new avenues for future therapeutic investigations.