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，在许多情况下， 随着活性氧（ROS）的产生增加，同时发生。但是，确切的 将感染/炎症与癌症联系起来的途径尚未很好地定义。我们的数据表明，诱导 多胺分解代谢酶的精子氧化酶（SMOX）通过感染/炎症会导致DNA损伤 ROS并引起癌变中观察到的变化； SMOX的抑制作用降低了 观察到的致癌变化。重要的是，我们有令人信服的数据，表明DNA损伤 由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 感染/炎症诱导的SMOX活性直接与癌变有关，并将SMOX定义为 化学预防的有吸引力的靶标。 SMOX的选择性抑制剂将具有巨大的价值作为研究 炎症/感染引起的致癌作用，并将其作为化学预防剂的潜力，但 不幸的是，没有这种抑制剂。鉴于这些事实，本申请的总体目标是确定 并测试可以用作工具化合物的SMOX的选择性抑制剂 化学预防剂。以下特定目标旨在追求这些目标。 目标1。使用类似物的化学合成，相似性搜索和 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，然后对选定化合物的命中至铅优化 治疗潜力。 目标2。评估新合成的化合物的选择性抑制和改变的能力 细胞反应。该特定目的的目的是识别具有选择性抑制活性的化合物 针对SMOX几乎没有或没有抑制性活性，以抗依赖FAD依赖性胺氧化酶， 包括MAOS和LSD1。在此目标中，我们将确定选定的酶抑制性动力学曲线 类似物，我们将确定这些类似物在体外抑制SMOX的细胞效应。 目标3。评估体内Smox抑制剂的有效性。作为该提议的主要目的是 确定具有化学预防剂潜力的SMOX的有效和选择性抑制剂，这是至关重要的 它们在相关的癌变模型中表现出有效性。我们将使用我们的ETBF/min鼠标 幽门螺杆菌诱导的胃癌的结肠肿瘤发生模型和蒙古gerbil模型，因为我们已经 先前发表的，以确定新鉴定的SMOX抑制剂的体内抗癌有效性。