Discovery could lead to drug therapy for hypopigmentation conditions

An NSAID-related compound called ampyrone appears to safely boost production of the pigment melanin in human skin, according to a preclinical study led by Weill Cornell Medicine and National Eye Institute investigators.

The discovery could lead to the development of an ampyrone-derived treatment for hypopigmentation disorders.

Such disorders, which include severe genetic forms of oculocutaneous albinism (OCA) as well as inflammation-caused hypopigmented skin patches, are characterized by abnormally low or even zero levels of melanin in cells. The lack of this ultraviolet-absorbing and antioxidant pigment can result in increased skin cancer risk, vision impairments due to improper retinal development and social difficulties.

The study, published June 18 in JCI Insight, was led by Dr. Jonathan Zippin, associate professor of dermatology at Weill Cornell Medicine; and Dr. Brian Brooks, chief of the Ophthalmic Genetics and Visual Function Branch at the National Eye Institute, part of the National Institutes of Health.

"Pharmacologic enhancement of human pigmentation represents a promising strategy for the treatment of diseases of hypopigmentation such as OCA by protecting skin, improving visual function and enhancing patient quality of life," said Zippin, who is also a dermatologist at NewYork-Presbyterian/Weill Cornell Medical Center.

"Improving melanin pigmentation in the eyes of people with OCA could potentially help them with difficulties such as glare sensitivity and, if initiated early enough, with developing better vision," Brooks said.

For the study, the researchers developed a platform to test compounds' ability to boost the activity of tyrosinase, an enzyme critical for melanin production in cells. Tyrosinase inhibitors are already widely used in skin lightening products and treatments for excessive pigmentation, but tyrosinase activators have posed a much greater challenge.

In prior research, Brooks and his team overcame a major technical barrier by developing a soluble, catalytically active form of human tyrosinase. This advance enabled the purification of large quantities of functional enzyme, and the development of a high-throughput, chemical-optical assay, which they used to screen more than 34,000 compounds for modulators of tyrosinase activity. The screen identified seven potential activators and 65 potential inhibitors, including 32 novel compounds.

More intensive testing revealed ampyrone as the most promising activator. The compound significantly increased the catalytic activity of both normal and albinism-causing mutant tyrosinase. It also rapidly boosted melanin production in cell models and a 3D skin model. No toxicity signs arose despite three weeks of exposure in some tests - unsurprisingly, since ampyrone, a derivative of an NSAID-type analgesic drug called aminopyrine, is known to have a good safety profile.

Leveraging a new liquid chromatography-mass spectrometry-based method for measuring immediate changes in melanin synthesis developed at Weill Cornell Medicine, Zippin and his team found that ampyrone was able to induce new melanin synthesis within an hour, demonstrating the potency of this drug and also suggesting that this new method for measuring melanin synthesis is applicable for in-cell screening for pigment-altering drugs.

The researchers are now using ampyrone as a "lead compound" or starting point for the development of a tyrosinase activator drug.

The research reported in this story was supported in part by the Intramural Research Program of the National Institutes of Health, the National Eye Institute, the National Center for Advancing Translational Sciences and the National Institute for Arthritis and Musculoskeletal and Skin Diseases. Additional support was provided by the Vision for Children Foundation, the National Organization for Albinism and Hypopigmentation Established Researcher Program Grant.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Jonathan Zippin.

Jim Schnabel is a freelance writer for Weill Cornell Medicine.