Monobenzone, a Novel and Potent KDM1A Inhibitor, Suppresses Migration of Gastric Cancer Cells.

Peizhi Ma,Gang Jia,Zhiyu Song

doi:10.3389/fphar.2021.640949

Peizhi Ma, Gang Jia + Show 1 more

Open Access

https://doi.org/10.3389/fphar.2021.640949

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Abstract

Lysine-specific demethylase1 (KDM1A) is generally highly expressed in various cancer tissues, and promotes the initiation and development of cancers via diverse cellular signaling pathways. Therefore, KDM1A is a promising drug target in many cancers, and it is crucial to find effective KDM1A inhibitors, while none of them has entered into market. With the help of compound library, monobenzone, a local depigmentor using as a treating over-pigmentation in clinic, was characterized as an effective KDM1A inhibitor (IC50 = 0.4507 μM), which may competitively inhibit KDM1A reversibly. Further cellular study confirmed that monobenzone could inhibit the proliferation of gastric cancer cell lines MGC-803 and BGC-823 with IC50 as 7.82 ± 0.55 μM and 6.99 ± 0.51 μM, respectively, and erase the substrate of KDM1A, H3K4me1/2 and H3K9 me2, and inhibit the migration of gastric cancer cell by reversing epithelial–mesenchymal transition (EMT). As the structure of monobenzone is very simple and small, this study provides a novel backbone for the further optimization of KDM1A inhibitor and gives monobenzone potential new application.

Highlights

Monobenzone is a potent skin-bleaching agent in melanoma patients (van den Boorn et al, 2011)
To discover KDM1A inhibitor with novel skeleton, an Food and Drug Administration (FDA) approved drug library containing 1971 compounds from APExBIO was subjected to KDM1A inhibitor screening assay
The 12 compounds with inhibitory rate more than 50% were collected and subjected to KDM1A inhibitor screening assay with H2O2 instead of KDM1A recombinant, so that false positive compound that can react with H2O2 or horseradish peroxidase (HRP) can be excluded

Summary

INTRODUCTION

Monobenzone is a potent skin-bleaching agent in melanoma patients (van den Boorn et al, 2011). Thereby, discovery of KDM1A inhibitor with new skeleton is in needed. In this manuscript, monobenzone was characterized as a reversible KDM1A inhibitor (IC50 0.4507 μM) from an U.S Food and Drug Administration (FDA) approved drug library from APExBIO using a drug repositioning strategy. We found that monobenzone can inhibit gastric cancer migration by reversing epithelial–mesenchymal transition (EMT). All these studies indicated that monobenzone may be considered as a novel skeleton as KDM1A inhibitor for further optimization and used to inhibit gastric cancer cell migration

MATERIALS AND METHODS

RESULTS

DATA AVAILABILITY STATEMENT