Ampyrone (4-Aminoantipyrine) is a Direct Agonist of Human Tyrosinase and Potential Therapeutic for Oculocutaneous Albinism and Disorders of Hypopigmentation.

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 unique human TYR construct, high-throughput screening, and computational analysis techniques, we identified ampyrone as a TYR activator. Ampyrone increased the in vitro catalytic activity of the intramelanosomal domain of human TYR (hTYR) and its hypomorphic variant, P406L, a cause of oculocutaneous albinism type 1B (OCA1B). Moreover, ampyrone induced melanin synthesis in both wild-type and OCA1B human melanocytes, as well as 3-dimension (3D) human skin cultures. Our results reveal ampyrone as a lead compound for first-in-class TYR activators, potentially accelerating the discovery of novel therapies for patients with genetic and acquired diseases of hypopigmentation.