Epigenetics Probes: Production of histone modifying enzymes and identification o

描述（由申请人提供）：组蛋白修饰酶的生产和鉴定用于表观遗传发现的化学探针基因组功能是最常见疾病的主要因素。基因组功能受组蛋白翻译后甲基化和乙酰化状态的调节。组蛋白是在细胞核中发现的蛋白质，其产生DNA结构化的核小体。修饰组蛋白的酶代表了癌症、神经退行性疾病、心血管和代谢疾病等适应症的重要潜在药物靶标。催化这些修饰的酶包括许多组蛋白甲基转移酶和脱甲基酶（“MT's”和“DMT's”）。此外，识别或“读取”这些组蛋白修饰的蛋白质含有溴结构域、染色质结构域等，并且也被认为是表观遗传因子。如果医学要超越仅代表对症治疗的传统药物靶点，那么验证这些表观遗传酶和因子作为药物靶点仍然是药物发现的首要任务。化学表观遗传抑制剂在这里代表了一个强大的机会。然而，组蛋白甲基化是一个相对较新的发现空间，MT或DMT抑制剂的可能结构尚不清楚。很少有小分子抑制剂可用于实验室研究或铅开发。因此，有一个显着的和迫切的需要，以开发检测和确定新的化学探针，这些目标。小分子探针将在科学研究中发挥有价值的作用，并作为药物化学支架用于铅的开发。在这项提案中，我们将部署一种宽领域高通量筛选（HTS）方法，通过测试1400多种特权支架，包括大多数FDA批准的药物和临床试验药物，以对抗30多种组蛋白修饰酶，包括HMT和组蛋白脱甲基酶（HDMT）。我们的初步研究已经证明了非常积极的结果，通过识别和确认对少数选定的HMT的命中。具有已知口服活性和相对安全的化合物的宽场HTS为化学探针发现提供了许多优点：（1）任何新鉴定的活性化合物将具有已知的科学药理学以支持新的应用;（2）这些探针具有实现“药物拯救”或“药物再利用”的潜力;（3）对于已经上市的化合物，新的表观遗传活性信息将有助于在没有数据的表观遗传水平上加深对其有效性或毒性的理解;（4）对于目前在临床试验中或在后期临床试验中失败的化合物，新的信息将提供指导以修改这些化合物以获得更好的定向治疗效果，和（5）这些数据将有助于建立通用化学表观基因组数据库。拥有一个公开的表观遗传抑制剂库对于在这一领域取得进展至关重要。

DESCRIPTION (provided by applicant): Production of histone modifying enzymes and identification of chemical probes for epigenetic discovery Genomic function is the major factor in the most common diseases. Genomic function is regulated by the posttranslational methylation and acetylation state of histones. Histones are proteins found in cell nuclei that create nucleosomes into which DNA is structured. Enzymes that modify histones represent important potential drug targets for indications like cancers, neurodegenerative disorders, cardiovascular, and metabolic diseases. Enzymes that catalyze these modifications include numerous histone methyltransferases and demethylases ("MT's" & "DMT's"). Additionally, proteins that recognize or "read" these histone modifications contain bromodomains, chromodomains, etc. and are also considered epigenetic factors. If medicine is to move beyond conventional drug targets that represent symptomatic treatment only, then validation of these epigenetic enzymes and factors as drug targets remains a top priority for drug discovery. Chemical epigenetic inhibitors represent a powerful opportunity here. However, histone methylation is a relatively new discovery space, and the likely structures of MT or DMT inhibitors are not yet known. Few small molecule inhibitors are available, either for laboratory research or for lead development. Therefore, there is a significant and urgent need to develop assays and to identify new chemical probes for these targets. Small molecule probes would serve a valuable role in scientific investigations and serve as medicinal chemistry scaffolds for lead development. In this proposal, we will deploy a wide-field high throughput screening (HTS) approach by testing more than 1400 privileged scaffolds that include most FDA approved drugs and clinical trial agents against over 30 histone modifying enzymes, including HMTs and histone demethylases (HDMTs). Our preliminary studies have already demonstrated very positive results by identifying and confirming hits against a handful of selected HMTs. Wide-field HTS with known orally active and relatively safe compounds offers a number of advantages for chemical probe discovery: (1) any newly identified active compound will have a known scientific pharmacology to support new applications; (2) these probes have the potential to enable "drug rescue" or "drug repurposing"; (3) for compounds already on the market, the new epigenetic activity information will help to provide enhanced understanding of their effectiveness or toxicity at the epigenetic level where no data was available; (4) for the compounds that are currently in clinical trials or have failed i late stage clinical trials, the new information will provide guidance to modify these compounds for better directed therapeutic effectiveness, and (5) this data will help establish a general chemo-epigenomic database. Having a publicly available library of epigenetic inhibitors is essential to moving ahead in this area.