Transcriptional Mechanism of BRD4 in Solid Tumor

BRD4在实体瘤中的转录机制

• 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
• 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

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.

项目总结 BRD4是一种主要的BET(溴和额外末端)家族转录调节因子，在转录过程中起着关键作用 乙酰赖氨酸串联结合在染色质中的有序基因转录 溴域(BRD)。BRD4被广泛认为是一种很有前途的抗癌药物靶点 使用BET BRD抑制剂的研究，其中一些正在进行人体临床试验 癌症。然而，BET抑制剂大多对造血癌有效，但要少得多。 因此，在实体肿瘤中，包括乳腺癌。开场白的问题是，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，并且高度敏感。 细胞类型和肿瘤类型。我们最近的研究表明，BRD4 在染色质中调节转录可能比目前简单的 BRD与乙酰化组蛋白和转录蛋白结合，并受上下文的影响- 依赖于其串联BRD的协调活动。我们证明了一种构象优化的 同时抑制BRD4串联BRD的二价BET BRD抑制剂提供 阻断BRD4与增强子/增强子的关联持续抑制BRD4转录活性 效力远优于单价BET抑制剂的介体蛋白，导致抑制 实体瘤细胞的增殖，包括一组三阴性乳腺癌(TNBC) 细胞，甚至对JQ1耐药的TNBC细胞。我们的研究提供了直接的实验证据 细胞类型和上下文依赖的BRD4在癌症中的作用并提示一种新的治疗方法 最大限度地控制BRD4活性的策略 作为毁灭性的TNBC，目前缺乏有针对性的治疗。受到我们充满希望的新产品的激励 发现，在这个项目中，我们将开发下一代BRD4选择性二价BRD抑制剂 并表征了BRD4作为一种新的基因的转录机制和治疗潜力 针对TNBC的靶向治疗。