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

DNA含有制造一个物种所有蛋白质的指令。为了进入细胞核，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。常染色质是轻装的，可用于基因表达，而异染色质是致密的，不能用于转录。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和组蛋白上安装和移除称为表观遗传标记的小片段，染色质重塑复合物改变其形状。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）是表观遗传阅读器，其与组蛋白上的乙酰化赖氨酸侧链相互作用并募集转录因子以启动基因的转录。BCP在许多癌症中被发现过表达，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，从而阻止了癌基因的表达。然而，大多数BCP抑制剂具有共同的结构，因此预计将遭受相同的责任。因此，迫切需要新的BCP抑制剂来提供对抗癌症的新的和替代的策略。该项目的目标是开发一种BPC抑制剂，BPC是开关/蔗糖非发酵SWI/SNF染色质重塑复合物的一部分，这是一种未开发的药物化学靶点，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表观遗传学有限公司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的互补领域。该项目将有助于培训高素质的人员，这些人员将能够在加拿大生物制药公司从事具有挑战性的工作，并促进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可能创造就业机会的新计划。最终，该项目可能导致治疗癌症的新策略，从而为加拿大人的健康做出贡献。

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.