Identification of novel spermine oxidase (SMOX) inhibitors as probes for an emerging chemoprevention target

鉴定新型精胺氧化酶 (SMOX) 抑制剂作为新兴化学预防靶标的探针

• 批准号: 9288140
• 负责人: Robert A. Casero
• 金额: $ 64.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-06 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9288140
• 关键词: Affect; Carcinogenesis Inhibition; Carcinoma; Chemoprevention; Chemopreventive Agent; Collection; Colon Carcinoma; Complex; DNA Damage; Data; Dose-Limiting; Drug Kinetics; Effectiveness; Enzymes; Epigenetic Process; Etiology; Genes; Genetic Transcription; Gerbils; Goals; Helicobacter pylori; Homology Modeling; Human; Hydrogen Peroxide; In Vitro; Incidence; Infection; Inflammation; KDM1A gene; Kinetics; Lead; Light; Link; Malignant Neoplasms; Modeling; Molecular; Monoamine Oxidase; Mus; Oxidases; Pathway interactions; Patients; Pharmaceutical Chemistry; Polyamines; Production; Proteins; Publishing; Putrescine; Reactive Oxygen Species; Recruitment Activity; Roentgen Rays; Role; Sampling; Spermine; Structure; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Transcription Repressor/Corepressor; Triazoles; amine oxidase; analog; base; carcinogenesis; carcinogenicity; chemical synthesis; chromatin remodeling; colon tumorigenesis; design; in vivo; inhibitor/antagonist; malignant stomach neoplasm; novel; polyamine oxidase; response; scaffold; small molecule; tool; tumor; tumorigenesis

Inflammation/infection has been implicated in the origin of 20-30% of epithelial cancers and, in many cases, occurs concurrently with increased production of reactive oxygen species (ROS). However, the precise pathways linking infection/inflammation to cancer are not well defined. Our data demonstrate that induction of the polyamine catabolic enzyme spermine oxidase (SMOX) by infection/inflammation produces DNA-damaging ROS and causes changes observed in carcinogenesis; inhibition of SMOX reduces the incidence of the observed carcinogenic changes. Importantly, we have compelling data indicating that the DNA damage induced by ROS leads to epigenetic transcriptional silencing. These data identify a molecular pathway in which infection/inflammation-induced SMOX activity is directly linked to carcinogenesis and define SMOX as an attractive target for chemoprevention. Selective inhibitors of SMOX would be of great value as probes to study inflammation/infection-induced carcinogenesis and would hold potential as chemopreventive agents, but, unfortunately, no such inhibitors exist. In light of these facts, the overall goals of this application are to identify and test selective inhibitors of SMOX that can serve as tool compounds and leads for the identification of chemopreventive agents. The following Specific Aims are designed to pursue these goals. Aim 1. To identify inhibitors of SMOX using chemical synthesis of analogues, similarity searching, and structure-based design techniques. We will use multiple medicinal chemistry approaches to identify and synthesize potential inhibitors of SMOX, followed by hit-to-lead optimization of selected compounds with therapeutic potential. Aim 2. To evaluate newly synthesized compounds for the ability to selectively inhibit SMOX and alter cellular response. The goal of this specific aim is to identify compounds that have selective inhibitory activity against SMOX with little or no inhibitory activity against closely related FAD-dependent amine oxidases, including the MAOs and LSD1. In this aim, we will determine the enzyme inhibitory kinetic profile for selected analogues, and we will determine the cellular effects of SMOX inhibition by these analogues in vitro. Aim 3. To evaluate the effectiveness of SMOX inhibitors in vivo. As the primary purpose of this proposal is to identify effective and selective inhibitors of SMOX that have potential as chemopreventive agents, it is critical that they demonstrate effectiveness in a relevant carcinogenesis model. We will use our ETBF/Min mouse colon tumorigenesis model and a Mongolian gerbil model for H. pylori-induced gastric cancer, as we have previously published, to determine the in vivo anticancer effectiveness of newly identified SMOX inhibitors.

炎症/感染与 20-30% 的上皮癌的起源有关，并且在许多情况下， 与活性氧（ROS）产生增加同时发生。然而，准确的 将感染/炎症与癌症联系起来的途径尚未明确。我们的数据表明，感应 多胺分解代谢酶精胺氧化酶 (SMOX) 通过感染/炎症产生 DNA 损伤 ROS 并引起致癌作用中观察到的变化；抑制 SMOX 可降低以下情况的发生率 观察到致癌变化。重要的是，我们有令人信服的数据表明 DNA 损伤 ROS 诱导导致表观遗传转录沉默。这些数据确定了一个分子途径，其中 感染/炎症诱导的 SMOX 活性与癌发生直接相关，并将 SMOX 定义为 化学预防的有吸引力的目标。 SMOX 的选择性抑制剂作为探针具有重要的研究价值 炎症/感染诱发的致癌作用，并且具有作为化学预防剂的潜力，但是， 不幸的是，不存在这样的抑制剂。鉴于这些事实，该应用程序的总体目标是确定 并测试 SMOX 的选择性抑制剂，该抑制剂可以作为工具化合物和先导化合物来鉴定 化学预防剂。以下具体目标旨在实现这些目标。 目标 1. 通过类似物的化学合成、相似性搜索和分析来鉴定 SMOX 抑制剂 基于结构的设计技术。我们将使用多种药物化学方法来识别和 合成 SMOX 的潜在抑制剂，然后对选定的化合物进行从命中到先导的优化 治疗潜力。 目标 2. 评估新合成的化合物选择性抑制 SMOX 和改变 细胞反应。这一具体目标的目的是鉴定具有选择性抑制活性的化合物 对抗 SMOX，对密切相关的 FAD 依赖性胺氧化酶具有很少或没有抑制活性， 包括 MAO 和 LSD1。为此，我们将确定选定的酶抑制动力学曲线 类似物，我们将在体外确定这些类似物抑制 SMOX 的细胞效应。 目标 3. 评估 SMOX 抑制剂的体内有效性。由于该提案的主要目的是 识别具有化学预防潜力的有效且选择性的 SMOX 抑制剂至关重要 它们在相关的致癌模型中表现出有效性。我们将使用 ETBF/Min 鼠标 结肠肿瘤发生模型和幽门螺杆菌诱导的胃癌的蒙古沙鼠模型，正如我们所研究的 先前发表的，以确定新鉴定的 SMOX 抑制剂的体内抗癌有效性。