Researchers have designed a small-molecule SIK inhibitor capable of penetrating human skin, which could lead the way to a ‘sunless tan’ that has the potential to reduce the risk of skin cancer. The molecule, developed at Massachusetts General Hospital and the Dana-Farber Cancer Institute, bypasses the defective receptor that prevents many fair-skinned people from tanning and stimulates melanin production further down the line.
Exposure to ultraviolet light doesn’t always lead to tanning in fair-skinned individuals because many of them lack a functional melanocortin 1 receptor (MC1R). Researchers originally believed this receptor and the hormone that stimulates it—MC1R ligand melanocyte stimulating hormone (MSH)—were necessary to produce melanin in response to UV light exposure.
Previous research showed they could stimulate the pigmentation in mice that didn’t have a functional receptor by applying forskolin, a cyclic AMP agonist. The mice produced pigment without the functioning receptor, but this earlier molecule wouldn’t penetrate thicker human skin to have the same effect.
The team turned to SIK inhibitors which, like forskolin, work on the same pathway further down the line than the Mc1R receptors. SIK inhibitors were known to produce the same outcome by enhancing expression of the MITF transcription factor, which regulates expression of enzymes that promote biosynthesis of melanin.
Once the team showed that the SIK inhibitor had stimulated the pathway to produce melanin in red-haired mice — who, like red-haired humans, generally don’t tan — they worked with Nathaneal Gray, vice chair of research in pediatric oncology at Dana Farber, to find a small molecule SIK inhibitor that was able to penetrate human skin. They rubbed the drug onto skin samples for eight days, and showed a gradual darkening of the skin. After they stopped, there was a gradual lightening — just like a real tan.
If the molecule graduates into the clinic, it’ll face long odds against an unyielding late-stage failure rate. Should it become a product, some consumers might find this molecule appealing for cosmetic reasons, as it creates a tan using the body’s natural mechanism for coloring skin.
Except MGH researcher David Fisher tells BBC News: “[Our] real goal is a novel strategy for protecting skin from UV radiation and cancer … dark pigment is associated with a lower risk of all forms of skin cancer — that would be really huge.”
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