Development of a Selective Bromodomain Inhibitor Involved in the SWI/SNF Chromatin Remodeling Complex

开发参与 SWI/SNF 染色质重塑复合物的选择性溴结构域抑制剂

• 批准号: 543520-2019
• 负责人: Gagnon, Alexandre
• 金额: $ 2.19万
• 依托单位: Université du Québec à Montréal
• 依托单位国家: 加拿大
• 项目类别: Collaborative Research and Development Grants
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683423
• 关键词: Development; Selective; Bromodomain; Inhibitor; Involved

The DNA contains the instructions for making all the proteins of a species. To fit inside the nucleus of a cell, the DNA wraps itself around proteins called histones, leading to the formation of chromatin. Euchromatin is lightly packed and available for gene expression whereas heterochromatin is dense and not accessible for transcription. The way chromatin is packed is regulated by epigenetic enzymes that install and remove small fragments called epigenetic marks on DNA and histones and by chromatin remodeling complexes that change its shape. Epigenetic readers interact with these marks to initiate gene transcription. Bromodomain containing proteins (BCPs) are epigenetic readers that interact with acetylated lysine side chains on histones and that recruit transcription factors to launch the transcription of genes. BCPs were found to be overexpressed in many cancers, leading to elevated expression of cancer-associated genes. Interaction of small molecules with BCPs disrupts their interaction with histones thus preventing the expression of oncogenes. However, most BCPs inhibitors share a common structure and are thus expected to suffer from the same liabilities. Therefore, new BCPs inhibitors are urgently needed to provide novel and alternative strategies to combat cancer. The goal of this project is to develop an inhibitor of BPCs that are part of the switch/sucrose nonfermenting SWI/SNF chromatin remodeling complex, an underexplored medicinal chemistry target that will be used as a chemical probe to investigate the role of SWI/SNF in gene expression. This project involves a multidisciplinary team of scientists at UQAM in Montreal and Zenith Epigenetics Ltd. in Calgary in the complementary fields of synthetic and medicinal chemistry, biology, biochemistry, biophysics and pharmacology. This project will contribute to the training of highly qualified personnel that will be able to take on challenging jobs in Canadian biopharmaceutical companies and to the advancement of knowledge in the field of epigenetics that will be used by the industrial partner to develop new programs that could result in job creation. Ultimately, this project could lead to new strategies to treat cancer, thus contributing to the health of Canadians.

DNA 包含制造一个物种所有蛋白质的指令。为了适应细胞核，DNA 将自身包裹在称为组蛋白的蛋白质周围，从而形成染色质。常染色质堆积较轻，可用于基因表达，而异染色质密集，不易转录。染色质的包装方式受到表观遗传酶的调节，表观遗传酶在 DNA 和组蛋白上安装和去除称为表观遗传标记的小片段，并受到改变其形状的染色质重塑复合物的调节。表观遗传阅读器与这些标记相互作用以启动基因转录。含溴结构域蛋白 (BCP) 是表观遗传读取器，可与组蛋白上的乙酰化赖氨酸侧链相互作用，并招募转录因子来启动基因转录。人们发现 BCP 在许多癌症中过度表达，导致癌症相关基因的表达升高。小分子与 BCP 的相互作用会破坏它们与组蛋白的相互作用，从而阻止癌基因的表达。然而，大多数 BCP 抑制剂具有共同的结构，因此预计会承担相同的责任。因此，迫切需要新的 BCP 抑制剂来提供新的替代策略来对抗癌症。该项目的目标是开发一种 BPC 抑制剂，它是开关/蔗糖非发酵 SWI/SNF 染色质重塑复合物的一部分，这是一种尚未充分开发的药物化学靶标，将用作化学探针来研究 SWI/SNF 在基因表达中的作用。该项目涉及蒙特利尔 UQAM 和卡尔加里 Zenith Epi Genetics Ltd. 的多学科科学家团队，涉及合成和药物化学、生物学、生物化学、生物物理学和药理学等互补领域。该项目将有助于培训高素质人员，使他们能够在加拿大生物制药公司承担具有挑战性的工作，并促进表观遗传学领域知识的进步，工业合作伙伴将利用这些知识来开发可能创造就业机会的新项目。最终，该项目可能会带来治疗癌症的新策略，从而为加拿大人的健康做出贡献。