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

基本信息

批准号：
9924482
负责人：
Robert A. Casero
金额：
$ 60.74万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-06 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924482
关键词：
Affect Carcinogenesis Inhibition Carcinoma Chemoprevention Chemopreventive Agent Collection Colon Carcinoma DNA Damage Data Dose-Limiting Drug Kinetics Effectiveness Enzymes Epigenetic Process Etiology Gene Silencing Genes Gerbils Goals Helicobacter pylori induced gastric cancer Homology Modeling Hydrogen Peroxide In Vitro Incidence Infection Inflammation KDM1A gene Kinetics Light Link Malignant Neoplasms Modeling Molecular Monoamine Oxidase Mus Oxidases Pathway interactions Patients Pharmaceutical Chemistry Polyamines Production Proteins Publishing Putrescine Reactive Oxygen Species Repressor Proteins Roentgen Rays Role Sampling Spermine Structure Techniques Testing Therapeutic Tissues Toxic effect Transcription Repressor Triazoles amine oxidase analog anti-cancer base carcinogenesis carcinogenicity chemical synthesis chromatin remodeling colon tumorigenesis design effectiveness evaluation human model in vivo inhibitor/antagonist lead optimization malignant stomach neoplasm novel polyamine oxidase recruit response scaffold small molecule tool tumor tumorigenesis

项目摘要

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。我们将使用我们的 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。

项目成果

期刊论文数量（21）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting polyamine metabolism for cancer therapy and prevention.

DOI：
10.1042/bcj20160383
发表时间：
2016-10-01
期刊：
The Biochemical journal
影响因子：
0
作者：
Murray-Stewart TR;Woster PM;Casero RA Jr
通讯作者：
Casero RA Jr

Self-Assembled Alkylated Polyamine Analogs as Supramolecular Anticancer Agents.

DOI：
10.3390/molecules27082441
发表时间：
2022-04-10
期刊：
Molecules (Basel, Switzerland)
影响因子：
0
作者：
通讯作者：

Polyamine-Based Nanostructures Share Polyamine Transport Mechanisms with Native Polyamines and Their Analogues: Significance for Polyamine-Targeted Therapy.

DOI：
10.3390/medsci10030044
发表时间：
2022-08-22
期刊：
Medical sciences (Basel, Switzerland)
影响因子：
0
作者：
Holbert, Cassandra E.;Foley, Jackson R.;Yu, Ao;Stewart, Tracy Murray;Phanstiel, Otto;Oupicky, David;Casero, Robert A.
通讯作者：
Casero, Robert A.

Helping the helpers: polyamines help maintain helper T-cell lineage fidelity.

DOI：
10.1097/in9.0000000000000002
发表时间：
2022-07
期刊：
Immunometabolism (Cobham, Surrey)
影响因子：
0
作者：
通讯作者：

Expanded Potential of the Polyamine Analogue SBP-101 (Diethyl Dihydroxyhomospermine) as a Modulator of Polyamine Metabolism and Cancer Therapeutic.

DOI：
10.3390/ijms23126798
发表时间：
2022-06-18
期刊：
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
影响因子：
5.6
作者：
Holbert, Cassandra E.;Foley, Jackson R.;Stewart, Tracy Murray;Casero, Robert A., Jr.
通讯作者：
Casero, Robert A., Jr.