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

描述（由申请人提供）：受调节的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网络中断与一系列人类癌症相关。这些疾病的核心通常是转录激活因子发生故障，这些蛋白质与特定基因相关，并将它们打开，从而产生它们编码的蛋白质。这代表了通过鉴定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疗法的机会。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-κ B（p50/p65异源二聚体））功能的小（药物样）分子，这两种转录激活因子与约30%的乳腺癌有关。通过体外和体内研究的结合，这些分子将被评估为单独和组合在阻断ErbB 2（Her 2）阳性乳腺癌的生长和转移的有效性，并提供其作用机制的详细了解。从更广泛的角度来看，本研究中确定的转录抑制剂将是解剖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，这里鉴定的分子将是原型转录靶向治疗剂，为未来的治疗研究开辟新的途径。 公共卫生相关性：在这项建议中概述了两种互补的方法来确定小（药物样）分子，抑制两个转录激活因子的功能，涉及约30%的乳腺癌。这些分子将在乳腺癌的几个体外和体内模型中进行研究，以评估它们在选择性地阻止与转录激活因子相关的癌症生长方面的有效性，并详细了解它们的作用机制。这里确定的分子将是原型转录靶向治疗，为未来的治疗研究开辟新的途径。

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.