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

炎症/感染与20%-30%的上皮性癌症的起源有关，在许多情况下， 与活性氧物种(ROS)的产生增加同时发生。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，诱导 感染/炎症引起的多胺分解代谢酶精胺氧化酶(SMOX)产生DNA损伤 在致癌过程中观察到的ROS和引起的变化；SMOX的抑制降低了 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。这些数据确定了一种分子途径，其中 感染/炎症诱导的SMOX活性与癌症的发生直接相关，并将SMOX定义为 具有吸引力的化学预防目标。SMOX选择性抑制剂作为探针具有重要的研究价值 炎症/感染诱导的致癌作用，并有可能作为化学预防药物，但是， 不幸的是，不存在这样的抑制物。鉴于这些事实，本应用程序的总体目标是确定 以及测试选择性的SMOX抑制剂，这些抑制剂可以作为工具化合物和线索来鉴定 化学防护剂。以下是为实现这些目标而设计的具体目标。 目的1.通过类似物的化学合成、相似性搜索和分子生物学方法鉴定SMOX的抑制剂 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 合成潜在的SMOX抑制剂，然后对选定的化合物进行点击到领先的优化 治疗潜力。 目的2.评价新合成化合物选择性抑制SMOX和ALTER的能力 细胞反应。这一特定目标的目的是鉴定具有选择性抑制活性的化合物。 抗SMOX而对密切相关的FAD依赖的胺氧化酶几乎没有抑制活性， 包括MAO和LSD1。为了达到这个目的，我们将测定选定的 我们将在体外确定这些类似物对SMOX抑制的细胞效应。 目的3.评价SMOX抑制剂的体内药效。因为这项提议的主要目的是 寻找有效和选择性的SMOX抑制剂，具有潜在的化学预防作用，这是至关重要的 他们在相关的致癌模型中展示了有效性。我们将使用我们的ETBF/Min鼠标 幽门螺杆菌诱发胃癌的结肠肿瘤发生模型和蒙古沙鼠模型 之前发表的，以确定新发现的SMOX抑制剂的体内抗癌效果。

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.