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

DNA包含了制造一个物种的所有蛋白质的指令。为了适应细胞核，DNA将自己包裹在一种叫做组蛋白的蛋白质上，从而形成染色质。常染色质是轻包装的，可用于基因表达，而异染色质是密集的，不能用于转录。染色质堆积的方式是由表观遗传酶调节的，表观遗传酶在DNA和组蛋白上安装和移除被称为表观遗传标记的小片段，染色质重塑复合体改变其形状。表观遗传读卡器与这些标记相互作用，启动基因转录。含溴结构域蛋白（bcp）是一种表观遗传读取器，它与组蛋白上的乙酰化赖氨酸侧链相互作用，并招募转录因子启动基因转录。bcp在许多癌症中被发现过度表达，导致癌症相关基因的表达升高。小分子与bcp的相互作用破坏了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，因此预计会遭受相同的责任。因此，迫切需要新的bcp抑制剂来提供新的和替代的策略来对抗癌症。该项目的目标是开发一种BPCs抑制剂，BPCs是开关/蔗糖非发酵SWI/SNF染色质重塑复合体的一部分，这是一个尚未开发的药物化学靶点，将被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昆士兰大学和卡尔加里Zenith表观遗传学有限公司的多学科科学家团队，他们在合成和药物化学、生物学、生物化学、生物物理学和药理学等互补领域进行研究。该项目将有助于培养高素质人才，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，并有助于提高表观遗传学领域的知识，这些知识将被工业合作伙伴用于开发新的项目，从而创造就业机会。最终，这个项目可能导致新的战略来治疗癌症，从而有助于加拿大人的健康。

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.