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ResearchIn-Press PreviewDermatologyOphthalmology Open Access | 10.1172/jci.insight.202947

Ampyrone is a direct agonist of human tyrosinase and a potential therapeutic for hypopigmentation disorders

Monika B. Dolinska,1 Yuhong A. Wang,1 Nathan P. Coussens,2 Vijay K. Kalaskar,1 Zuhal Eraslan,3 Samuel J. Grondin,4 Joseph Bonica,3 Sarah Toay,1 Matthew D. Hall,2 Min Shen,2 Matthew Boxer,2 Qiuying Chen,4 Steven S. Gross,4 Nabeel Attarwala,4 Yingyos Jittayasothorn,1 Ramakrisha P. Alur,1 Dhyanam Shukla,1 Robin Kee,1 Charles DeYoung,1 Cuilee Sha,1 David R. Adams,5 Stacie K. Loftus,5 Tiziana Cogliati,1 Yuri V. Sergeev,1 Jonathan H. Zippin,3 and Brian P. Brooks1

1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

Find articles by Sergeev, Y. in: PubMed | Google Scholar

1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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1Ophthalmic Genetics and Visual Function Branch, National Eye Institute, NIH, Bethesda, United States of America

2National Center for Advancing Translational Sciences, NIH, Rockville, United States of America

3Department of Dermatology, Weill Cornell School of Medicine, New York, United States of America

4Department of Pharmacology, Weill Cornell School of Medicine, New York, United States of America

5National Human Genome Research Institute, NIH, Bethesda, United States of America

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Published June 18, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.202947.
Copyright © 2026, Dolinska et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 18, 2026 - Version history
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Abstract

Significant loss of pigmentation can increase visual disability, skin cancer risk, and psychosocial stress. Tyrosinase (TYR) catalyzes the first and rate-limiting step of melanin synthesis. Inhibitors of TYR are well established and are currently used in clinical settings; however, there is a dearth of direct activators of TYR. Here, using a human TYR construct, we developed high-throughput screening methods, in cell confirmatory assays employing 13C-tyrosine tracing, and computational analysis techniques, and identified ampyrone (4-aminoantipyrine) as a TYR activator. Ampyrone increased the in vitro catalytic activity of the human recombinant intra-melanosomal domain of TYR (hTYR) and its hypomorphic variant, Pro406Leu (P406L), a cause of oculocutaneous albinism type 1B (OCA1B). Moreover, ampyrone induced melanin synthesis in both wild-type and OCA1B human melanocytes, mouse OCA2 melanocytes, as well as 3-dimensional (3D) human skin cultures. Computational studies provided additional insight into the effects of direct TYR agonists on enzyme activity. Our results identified ampyrone as a lead candidate for TYR activation, potentially supporting the development of therapies for patients with genetic and acquired diseases of hypopigmentation.

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