Transcriptional Mechanism of BRD4 in Solid Tumor

BRD4在实体瘤中的转录机制

• 批准号: 10358485
• 负责人: Ming-Ming Zhou
• 金额: $ 38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 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/10358485
• 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; 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

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.

项目摘要 BRD 4是一个主要的BET（bromo and extra terminal）家族转录调控因子，在转录调控中起着关键作用 在染色质中通过其特征性串联乙酰赖氨酸结合进行有序基因转录 溴结构域（BrD）。BRD 4被广泛认为是一种有前途的抗癌药物靶标， 使用BET BrD抑制剂的研究，其中一些正在人体临床试验中进行评估， 癌然而，BET抑制剂对造血系统癌症大多有效，但效果要差得多 包括乳腺癌在内的实体瘤也是如此。第一个问题是为什么化学抑制 这种通用的转录调节因子只影响有限数量的基因， 细胞和肿瘤类型。我们最近的研究表明，BRD 4 调控染色质转录的机制可能比目前简单的观点要复杂得多， BrDs与乙酰化组蛋白和转录蛋白结合并受环境影响- 依赖其串联BrD的协调活动。我们表明，构象优化， 同时抑制BRD 4的串联BrD的二价BET BrD抑制剂提供 通过阻断BRD 4与增强子的结合持续抑制BRD 4转录活性， 介体蛋白的效力远远上级单价BET抑制剂，导致抑制 包括一组三阴性乳腺癌（TNBC）的实体瘤细胞增殖 细胞，甚至JQ 1抗性TNBC细胞。我们的研究提供了直接的实验证据， 细胞类型和背景依赖性BRD 4在癌症中的功能，并提出了一种新的治疗方法 最大限度地控制快速实体瘤细胞增殖所需BRD 4活性的策略， 作为目前缺乏靶向治疗的毁灭性TNBC。受我们有前途的新 研究结果，在这个项目中，我们将开发下一代BRD 4选择性二价BrD抑制剂 并将BRD 4的转录机制和治疗潜力描述为一种新的 TNBC的靶向治疗。