A UV-Independent Topical Small-Molecule Approach for Melanin Production in Human Skin

Abstract

SUMMARYThe presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in “redhaired” Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.

Synthetic biology-based cellular biomedical tattoo for detection of hypercalcemia associated with cancer

“…Melanin is insoluble and has a half-life of several weeks in the melanocytes of human skin (24). To validate whether a biomedical tattoo would remain visible for extended periods of time, we stored hypercalcemia-induced melanin-containing HEK Tattoo pellets for up to 6 months at room temperature.…”

A Topical Solution to the Sunless Tanning Problem

“…Work by Mujahid et al recently published in Cell Reports [2] describes how topical administration of first and second generation SIK inhibitors, HG 9-91-01 (HG), YKL 06-061 (YKL1) and YKL 06-062 (YKL2), can increase melanin production in vitro and in vivo. In vitro treatment with HG of normal human melanocytes and the human melanoma lines UACC62 and UACC257 resulted in increased expression of MITF mRNA and downstream MITF target TRPM1 mRNA, indicating that HG activated the melanin-producing pathway [2] .…”

“…In vitro treatment with HG of normal human melanocytes and the human melanoma lines UACC62 and UACC257 resulted in increased expression of MITF mRNA and downstream MITF target TRPM1 mRNA, indicating that HG activated the melanin-producing pathway [2] . In vivo , topical HG treatment induced local black eumelanin skin pigmentation in “red-headed” Mc1r -deficient K14-Scf mice, but not in albino K14-Scf mice [2].…”

“…In vitro treatment with HG of normal human melanocytes and the human melanoma lines UACC62 and UACC257 resulted in increased expression of MITF mRNA and downstream MITF target TRPM1 mRNA, indicating that HG activated the melanin-producing pathway [2] . In vivo , topical HG treatment induced local black eumelanin skin pigmentation in “red-headed” Mc1r -deficient K14-Scf mice, but not in albino K14-Scf mice [2]. Since HG is not easily absorbed through human skin, the Fisher laboratory used a kinase screen, identifying second generation SIK inhibitors YKL1 and YKL2, which exhibited similar kinase activity and predicted skin penetration better than other agents [2].…”

“…In vivo , topical HG treatment induced local black eumelanin skin pigmentation in “red-headed” Mc1r -deficient K14-Scf mice, but not in albino K14-Scf mice [2]. Since HG is not easily absorbed through human skin, the Fisher laboratory used a kinase screen, identifying second generation SIK inhibitors YKL1 and YKL2, which exhibited similar kinase activity and predicted skin penetration better than other agents [2]. YKL1 and YKL2 were used to treat human breast skin explants in vitro and induced melanin production and skin darkening.…”