KT ‐939: A Next‐Generation Human Tyrosinase Inhibitor With Superior Efficacy for the Safe Management of Hyperpigmentation

ABSTRACT Background Tyrosinase is the rate‐limiting enzyme in melanin biosynthesis, and its overactivity contributes to hyperpigmentation disorders. Existing tyrosinase inhibitors are often limited by poor potency against human tyrosinase (hTYR) or safety concerns. Aims To evaluate the inhibitory potency, safety, and multifunctional activity of KT‐939, a newly synthesized human tyrosinase inhibitor, compared with established depigmenting agents. Patients/Methods KT‐939 was synthesized and tested in vitro for tyrosinase inhibition, melanin suppression in human melanocytes, antioxidant activity (DPPH radical scavenging, NRF2 pathway activation), and anti‐inflammatory activity (cytokine expression in LPS‐stimulated macrophages). Safety was assessed in multiple skin‐related cell lines. A 28‐day, single‐center clinical study in healthy women with sensitive skin assessed the effects of 0.2% KT‐939 lotion on pigmentation and tolerability. Results KT‐939 strongly inhibited hTYR (IC₅₀ = 0.07 μM), demonstrating ~4‐fold greater potency than Thiamidol and far surpassing other comparators. In melanocytes, KT‐939 reduced melanin production (IC₅₀ = 0.36 μM) with reversible effects upon withdrawal. KT‐939 also displayed antioxidant activity, NRF2 activation, and suppression of pro‐inflammatory cytokines, without cytotoxicity up to 50 μM. Clinically, 28 days of KT‐939 lotion use improved skin spot lightening, tone uniformity, and overall brightness, with good tolerability in sensitive skin. Conclusions KT‐939 is a potent and safe human tyrosinase inhibitor with additional antioxidant and anti‐inflammatory activity. These findings support its potential in cosmetic skin brightening and as a therapeutic candidate for hyperpigmentation disorders.