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

• DOI: 10.1016/j.celrep.2017.05.042
• Publication Date: 2017-06-13T22:02:44Z
• Authors: Nisma Mujahid; Yanke Liang; Ryo Murakami; Hwan Geun Choi; Allison S. Dobry; Jinhua Wang; Yusuke Suita; Qing Yu Weng; Jennifer Allouche; Lajos V. Kemeny; Andrea L. Hermann; Elisabeth M. Roider; Nathanael S. Gray; David E. Fisher
• Keywords: Melanins; 0303 health sciences; QH301-705.5; Ultraviolet Rays; Administration, Topical; 610; 500; Mice, Transgenic; Article; 3. Good health; eumelanin; Mice, Inbred C57BL; Mice; 03 medical and health sciences; topical drug; Animals; Humans; pigmentation; microphthalmia-associated transcription factor (MITF); salt-inducible kinase (SIK); Biology (General); Skin

The 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.