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

描述(申请人提供)：受调控的基因表达对细胞的正常生长和发育是必不可少的。控制这一复杂过程的网络中断与一系列人类癌症有关。通常，这些疾病的核心是功能不正常的转录激活因子，即与特定基因相关的蛋白质，并将其激活，从而产生它们编码的蛋白质。这代表着一个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解决转录调控失调的治疗方法的机会。将使用两种互补的方法来识别抑制两种转录激活剂ESX和NF-kappaB(p50/p65异源二聚体)功能的小分子(类药物)，这两种转录激活剂与大约30%的乳腺癌有关。通过体外和体内研究的结合，这些分子将被单独和联合评估在阻断ErbB2(Her2)阳性乳腺癌的生长和转移方面的有效性，并提供对它们的作用机制的详细了解。从更广泛的角度来看，这项研究中确定的转录抑制物将是剖析转录错误与乳腺癌之间关系的优秀工具。我们对这些分子的研究也将被用来建立一个有效的转录抑制物应该表现出的特征(效力、有效性、特异性)的概况。通过这种方式，这里确定的分子将是转录靶向治疗的原型，为未来的治疗研究开辟新的途径。 公共卫生相关性：在这项提案中概述了两种互补的方法来识别小(类药物)分子，它们抑制了两种转录激活剂的功能，这两种转录激活剂与大约30%的乳腺癌有关。这些分子将在几个体外和体内乳腺癌模型中进行研究，以评估它们在选择性阻止与转录激活剂相关的癌症生长方面的有效性，并提供对其作用机制的详细了解。这里确定的分子将是转录靶向治疗的原型，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.