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

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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.