Screening of an Epigenetic Drug Library Identifies 4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-Phenyl-Benzeneacetamide that Reduces Melanin Synthesis by Inhibiting Tyrosinase Activity Independently of Epigenetic Mechanisms.

Hyerim Song,Yun Jeong Hwang,Jae Won Ha,Yong Chool Boo

doi:10.3390/ijms21134589

Hyerim Song, Yun Jeong Hwang + Show 2 more

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https://doi.org/10.3390/ijms21134589

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Abstract

The aim of this study was to identify novel antimelanogenic drugs from an epigenetic screening library containing various modulators targeting DNA methyltransferases, histone deacetylases, and other related enzymes/proteins. Of 141 drugs tested, K8 (4-((hydroxyamino)carbonyl)-N-(2-hydroxyethyl)-N-phenyl-benzeneacetamide; HPOB) was found to effectively inhibit the α-melanocyte-stimulating hormone (α-MSH)-induced melanin synthesis in B16-F10 murine melanoma cells without accompanying cytotoxicity. Additional experiments showed that K8 did not significantly reduce the mRNA and protein level of tyrosinase (TYR) or microphthalmia-associated transcription factor (MITF) in cells, but it potently inhibited the catalytic activity TYR in vitro (IC50, 1.1–1.5 µM) as compared to β-arbutin (IC50, 500–700 µM) or kojic acid (IC50, 63 µM). K8 showed copper chelating activity similar to kojic acid. Therefore, these data suggest that K8 inhibits cellular melanin synthesis not by downregulation of TYR protein expression through an epigenetic mechanism, but by direct inhibition of TYR catalytic activity through copper chelation. Metal chelating activity of K8 is not surprising because it is known to inhibit histone deacetylase (HDAC) 6 through zinc chelation. This study identified K8 as a potent inhibitor of cellular melanin synthesis, which may be useful for the treatment of hyperpigmentation disorders

Highlights

Human skin color is controlled by the composition and distribution of various chromophores such as melanin, hemoglobin, and carotenoids [1]
The library contains 141 cell-permeable small molecule drugs that modulate the activity of epigenetic enzymes including DNA methyltransferases, DNA demethylases, histone acetyltransferases, histone deacetylase (HDAC), or acetylated histone binding proteins
We examined whether K8 can reduce the gene expression levels of TYR and other related enzymes involved in melanin synthesis via the regulation of transcription factors such as microphthalmia-associated transcription factor (MITF)

Summary

Introduction

Human skin color is controlled by the composition and distribution of various chromophores such as melanin, hemoglobin, and carotenoids [1]. Melanin is a dark polymer pigment synthesized by melanocytes [2]. Melanosomes containing melanin migrate from melanocytes to neighboring keratinocytes via dendrites, resulting in the distribution of melanin throughout the epidermis [3]. Melanin plays an important role in protection against carcinogenic ultraviolet radiation [4]; melanin metabolism is critical in epidermal homeostasis [5,6]. Dysfunctions associated with melanin synthesis cause clinically relevant pigmentation disorders that can be congenital or acquired, cutaneous or systemic, temporary or permanent, and related to hypoInt. J.

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