Transcriptional Mechanism of BRD4 in Solid Tumor

BRD4在实体瘤中的转录机制

基本信息

批准号：
10089421
负责人：
Ming-Ming Zhou
金额：
$ 38.77万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10089421
关键词：
Acetylation Affect Amino Acids Antineoplastic Agents BRD2 gene Binding Biochemical Biology Breast Cancer Cell Bromodomain Cell Cycle Regulation Cell Proliferation Cells Characteristics Chemicals Chromatin Complex DNA Repair Data Dependence Disease Drug Targeting Enhancers Epigenetic Process Family Gene Activation Gene Order Genes Genetic Transcription Genomics Geometry Hematologic Neoplasms Histones Human In Vitro Inflammation Inflammatory Investigation Length Lysine Malignant Neoplasms Mediating Mediator of activation protein Molecular Molecular Conformation Nature Oncogenes Oncogenic Plant Roots Play Positive Transcriptional Elongation Factor B Property Proteins RNA Repression Research Resistance Role Signal Transduction Solid Neoplasm Structure Techniques Testis Therapeutic Transcription Coactivator Transcription Elongation Transcriptional Activation YY1 Transcription Factor acute myeloid leukemia cell base biophysical techniques cancer clinical trial cancer stem cell cancer therapy cell type cohesin combat design effective therapy gene repression inhibitor/antagonist insight malignant breast neoplasm member neoplastic cell next generation novel novel therapeutic intervention recruit targeted treatment therapy resistant tool transcription factor triple-negative invasive breast carcinoma tumor

项目摘要

PROJECT SUMMARY BRD4, a major BET (bromo and extra terminal) family transcription regulator, plays a pivotal role in ordered gene transcription in chromatin through its characteristic tandem acetyl-lysine binding bromodomains (BrDs). BRD4 is widely recognized as a promising anticancer drug target from studies using BET BrD inhibitors, some of which are being evaluated in human clinical trials for cancer. However, BET inhibitors are mostly effective in hematopoietic cancers, but much less so in solid tumors including breast cancers. The opening question is why chemical inhibition of this general transcription regulator affects only a limited number of genes and is highly sensitive to cell- and tumor-types. Our recent studies suggest that the mechanism by which BRD4 regulates transcription in chromatin is likely far more complex than the current simplistic view of BrDs binding to acetylated histones and transcription proteins and influenced by context- dependent coordinated activities of its tandem BrDs. We show that a conformationally optimized bivalent BET BrD inhibitor that simultaneously inhibits the tandem BrDs of BRD4 affords sustained repression of BRD4 transcriptional activity by blocking its association with enhancer/ mediator proteins with potency far superior to monovalent BET inhibitors, resulting in inhibition of proliferation of solid tumor cells including a panel of triple negative breast cancer (TNBC) cells and even JQ1 resistant TNBC cells. Our study provides direct experimental evidence on the cell-type and context dependent BRD4 functions in cancers and suggests a new therapeutic strategy to maximally control BRD4 activity required for rapid solid tumor cell proliferation such as the devastating TNBC that currently lacks targeted therapy. Motivated by our promising new findings, in this project, we will develop next-generation BRD4-selective bivalent BrD inhibitors and characterize the transcriptional mechanism and therapeutic potential of BRD4 as a new targeted treatment for TNBC.

项目概要 BRD4 是一个主要的 BET（溴和额外末端）家族转录调节因子，发挥着关键作用通过其特有的串联乙酰赖氨酸结合，在染色质中有序地进行基因转录溴结构域（BrD）。 BRD4被广泛认为是一个有前途的抗癌药物靶点使用 BET BrD 抑制剂进行的研究，其中一些正在人体临床试验中进行评估癌症。然而，BET 抑制剂对造血系统癌症大多有效，但效果较差在包括乳腺癌在内的实体瘤中也是如此。首先的问题是为什么化学抑制这种通用转录调节因子仅影响有限数量的基因，并且高度敏感细胞和肿瘤类型。我们最近的研究表明 BRD4 的机制调节染色质转录可能比目前简单的观点复杂得多 BrD 与乙酰化组蛋白和转录蛋白结合并受上下文影响其串联 BrD 的依赖协调活动。我们证明了构象优化二价 BET BrD 抑制剂同时抑制 BRD4 的串联 BrD 通过阻断 BRD4 与增强子的关联来持续抑制 BRD4 转录活性/ 介体蛋白的效力远远优于单价 BET 抑制剂，从而产生抑制作用实体瘤细胞的增殖，包括一组三阴性乳腺癌 (TNBC) 细胞，甚至 JQ1 耐药 TNBC 细胞。我们的研究提供了直接的实验证据细胞类型和环境依赖性 BRD4 在癌症中发挥作用，并提出了一种新的治疗方法最大限度地控制实体瘤细胞快速增殖所需的 BRD4 活性的策略，例如作为目前缺乏针对性治疗的毁灭性 TNBC。受到我们有前途的新产品的激励研究结果表明，在这个项目中，我们将开发下一代 BRD4 选择性二价 BrD 抑制剂并描述了 BRD4 作为新药物的转录机制和治疗潜力 TNBC 的靶向治疗。