Transcriptional Mechanism of BRD4 in Solid Tumor

BRD4在实体瘤中的转录机制

• 批准号: 10582673
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582673
• 关键词: Acetylation; Affect; Amino Acids; Antineoplastic Agents; BRD2 gene; Binding; Biochemical; Biology; Breast Cancer Cell; Bromodomain; Bromodomains and extra-terminal domain inhibitor; 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; Histone Acetylation; Human; In Vitro; Inflammation; Inflammatory; Investigation; Length; Lysine; Malignant Neoplasms; Mediating; Mediator; Molecular; Molecular Conformation; Nature; Oncogenes; Oncogenic; Phosphorylation; Play; Positive Transcriptional Elongation Factor B; Proliferating; 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; 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; tumor initiation

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 BRD4是一个主要的赌注（Bromo和额外终端）家庭转录器，起着关键作用 在染色质中通过其特征串联乙酰赖氨酸结合中的有序基因转录 溴化群（BRD）。 BRD4被广泛认为是有前途的抗癌药物靶标 使用BET BRD抑制剂的研究，其中一些正在人类临床试验中评估 癌症。但是，BET抑制剂大多在造血癌中有效，但要少得多 因此，在包括乳腺癌在内的实体瘤中。开场问题是为什么化学抑制 该一般转录调节剂仅影响有限数量的基因，并且高度敏感 到细胞和肿瘤类型。我们最近的研究表明BRD4的机制 调节染色质中的转录可能比当前的简单视图要复杂得多 BRD与乙酰化组蛋白和转录蛋白结合，受环境影响 - 其串联BRD的依赖协调活动。我们证明了一个构象优化的 二价赌注BRD抑制剂同时抑制BRD4的串联BRD 通过阻止其与增强子/ 具有效力的介质蛋白远高于单价下注抑制剂，导致抑制作用 实体瘤细胞的增殖，包括一组三重阴性乳腺癌（TNBC） 细胞甚至JQ1抗性TNBC细胞。我们的研究提供了有关的直接实验证据 细胞类型和上下文依赖性BRD4在癌症中的功能，并提出一种新的治疗性 快速实体瘤细胞增殖所需的最大控制BRD4活性的策略 由于目前缺乏有针对性的治疗的毁灭性TNBC。由我们有前途的新的动机 调查结果，在这个项目中，我们将开发下一代BRD4选择性二价BRD抑制剂 并将BRD4的转录机制和治疗潜力描述为新的 针对TNBC的目标治疗。