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

转录激活剂 ESX 和 NF-kB 的小分子抑制剂

基本信息

批准号：
8223254
负责人：
ANNA K. MAPP
金额：
$ 29.49万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-20 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8223254
关键词：
Activator Appliances Address Affect Apoptosis Binding Biological Assay Biological Factors Breast Cancer Cell Cancer cell line Cell Culture Techniques Cell surface Cells Characteristics Complex Disease Dose Effectiveness Exhibits Future Gene Expression Generations Generic Drugs Genes Genetic Genetic Transcription Growth Growth and Development function Head Cancer Heart Diseases Human In Vitro Individual Investigation Laboratories Lead Libraries Malignant Neoplasms Malignant neoplasm of pancreas Marines Mediating Messenger RNA Modeling Molecular NF-kappa B Neck Cancer Neoplasm Metastasis Normal tissue morphology Pathway interactions Pattern Pharmaceutical Preparations Phenotype Process Proteins Regulation Regulatory Pathway Reporter Reporting Resistance Roche brand of trastuzumab Screening procedure Signal Transduction Source Specificity TNFRSF5 gene Testing Therapeutic Therapeutic Agents Transcription Coactivator Transcription Initiation Transcriptional Activation Transcriptional Activation Domain Tyrosine Kinase Inhibitor base cell motility chemotherapy design genome-wide high throughput screening human disease hydrastine in vivo in vivo Model inhibitor/antagonist malignant breast neoplasm microorganism p65 prototype public health relevance receptor research study scaffold small molecule theories therapeutic target therapy development tool tumor tumor specificity

项目摘要

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.

描述（由申请人提供）：受调节的基因表达对于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的破坏与一系列人类癌症相关。这些疾病的核心通常是转录激活剂的故障，与特定基因相关并打开它们的蛋白质，以便产生它们编码的蛋白质。这代表了开发疗法的机会，通过鉴定直接抑制与乳腺癌相关的转录激活剂功能的分子来解决转录正调。将使用两种互补方法来识别抑制两个转录激活剂ESX和NF-KAPPAB（p50/p65异二聚体）的功能的小（药物样）分子，该功能约为乳腺癌的大约30％。通过体外和体内研究的结合，这些分子将被评估为单独的，并结合使用，以阻止ERBB2（HER2）阳性乳腺癌的生长和转移，并提供对其作用机理的详细理解。从更广泛的角度来看，本研究中确定的转录抑制剂将是剖析转录和乳腺癌之间关系的出色工具。我们对这些分子的研究也将用于建立有效转录抑制剂的特征（效力，功效，特异性）的特征。这样，这里确定的分子将是原型转录靶向疗法，为将来的治疗研究开辟了新的途径。公共卫生相关性：该提案中概述的是两种互补的方法，用于识别小（类似药物的）分子，这些分子抑制了大约30％的乳腺癌的两个转录激活剂的功能。这些分子将在几种体外和体内乳腺癌模型中进行研究，以评估其有效性，以选择性地停止与转录激活剂相关的癌症的生长，并详细了解其作用机理。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了新的途径。