The human tyrosinase is the most prominent therapeutic target for pigmentary skin disorders. However, the overwhelming majority efforts have been devoted to search mushroom tyrosinase inhibitors, which show poor inhibitory activity on human tyrosinase and certain side effects that cause skin damage in practical application. Herein, a series of degraders that directly targeted human tyrosinase was firstly designed and synthesized based on newly developed PROTAC technology. The best PROTAC TD9 induced human tyrosinase degradation obviously in dose and time-dependent manner, and its mechanism of inducing tyrosinase degradation has also been clearly demonstrated. Besides, encouraging results that low-toxicity PROTAC TD9 was applied to reduce zebrafish melanin synthesis have been obtained, highlighting the potential to treatment of tyrosinase-related disorders. Moreover, this work has innovatively expanded the application scope of PROTAC technology and laid a solid foundation for further development of novel drugs treating pigmentary skin disorders.

人酪氨酸酶是色素性皮肤病最突出的治疗靶点。然而，绝大多数的努力都致力于寻找蘑菇酪氨酸酶抑制剂，其对人体酪氨酸酶的抑制活性较差，在实际应用中具有一定的副作用，导致皮肤损伤。在此，基于新开发的PROTAC技术，首次设计合成了一系列直接靶向人体酪氨酸酶的降解剂。最佳PROTAC TD9诱导人酪氨酸酶降解明显呈剂量和时间依赖性，其诱导酪氨酸酶降解的机制也已得到明确证明。此外，令人鼓舞的结果是低毒 PROTAC TD9已获得用于减少斑马鱼黑色素合成的应用，突出了治疗酪氨酸酶相关疾病的潜力。此外，该工作创新性地扩大了PROTAC技术的应用范围，为进一步开发治疗色素性皮肤病的新药奠定了坚实的基础。