Background

Monobenzone (Figure 1) is the monobenzyl ether of hydroquinone used medically for depigmentation. Monobenzone occurs as a white, almost tasteless crystalline powder, soluble in alcohol and practically insoluble in water. It exerts a depigmenting effect on skin of mammals by increasing the excretion of melanin from the melanocytes. It may also cause destruction of melanocytes and permanent depigmentation.

Pharmacodynamics

Monobenzone is the monobenzyl ether of hydroquinone. Monobenzone, applied topically to the skin, is used as a depigmenting agent inhibitting melanin produced by polymerization of oxidation products of tyrosine and dihydroxyphenyl compounds. Monobenzone works by permanently removing color from normal skin located around skin with vitiligo.[1]

Mechanism of action

Monobenzone is a depigmenting agent whose mechanism of action is not fully understood. It is proposed that it increases the excretion of melanin from the melanocytes. This effect is erratic and may take one to four months to occur while existing melanin is lost with normal sloughing of the stratum corneum. Hyperpigmented skin appears to fade more rapidly than does normal skin, and exposure to sunlight reduces the depigmenting effect of the drug. Following skin depigmentation after topical application of monobenzone, the histological studies indicate similar results as that seen in vitiligo, where the epidermis is intact but with the absence of identifiable melanocytes.[2]

Discovery of Monobenzone as a Potent and Reversible KDM1A Inhibitor

Monobenzone is a potent skin-bleaching agent in melanoma patients. In 2018, it was also reported that monobenzone was applicable for the treatment of cutaneous melanoma metastases, indicating its additional clinical investigation value. Nevertheless, the mechanism of action behind the monobenzone is still unclear, and target of monobenzone has not been clarified. As reported, there is increasing evidence that histone lysine methylation plays a significant role in melanoma metastasis and other solid tumors, however, whether monobenzone may act as the regulator and inhibit cell metastasis by regulating histone methylation is not clear. [3]

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. 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. Further molecular docking indicated that monobenzone can penetrate into the active cavity of KDM1A by forming two hydrogen bonds with Arg316 and Thr624 residues. Additional cellular study indicated that KDM1A can bind and inhibit KDM1A in cells and induce the accumulation of KDM1A substrate H3K4me1/2 and H3K9me2. Finally, 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.[3]

In this study, monobenzone was first characterized as a KDM1A inhibitor, it can effectively repress KDM1A activity selectively in a reversible manner in biochemical level, and additional docking analysis indicated that monobenzone may penetrate into the cavity where FAD stands in KDM1A, of which it may form two hydrogen bonds with Arg316 and Thr624 residues, respectively. Further cellular study suggested that monobenzone can induce the accumulation of H3K4me1/2 and H3K9 me1/2 in either MGC-803 or BGC-823 cells in a dose dependent manner. Specifically, 5 μMmonobenzone performed similar induction effect of H3K4me1/2 and H3K9me1/2 as ORY-1001. In-depth analysis suggested that monobenzone showed strong inhibitory effect on migration ability of gastric cancer cells by reversing EMT. This finding endowed monobenzone with a new function as migration inhibitor. Based on this study, the biological application of monobenzone is no longer restricted to be a depigmentor, but indicating that monobenzone may serve as a novel skeleton for developing KDM1A inhibitors.[3]

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.

References

[1] FDA Approved Products: Benoquin (monobenzone) cream.

[2] Monobenzone: Uses, Interactions, Mechanism of Action | DrugBank Online  https://go.drugbank.com/drugs/DB00600

[3] Ma P, Jia G, Song Z. Monobenzone, a Novel and Potent KDM1A Inhibitor, Suppresses Migration of Gastric Cancer Cells. Front Pharmacol. 2021;12:640949. Published 2021 Apr 15. doi:10.3389/fphar.2021.640949