Discovery of a Potent, Selective, and Orally Efficacious STAT6 PROTAC for the Treatment of Atopic Dermatitis
Wentao Wang, Mengyu Zhao, Liuzhi Hu, Chenxi Wang, Zheyuan Shen, Rongkuan Jiang, Feifei Peng, Yuxuan Wang, Jinxin Che, Wenhai Huang, Mingfei Wu, Xiaowu DongAbstract
Signal transducer and activator of transcription 6 (STAT6), a key mediator of IL-4/IL-13 signaling, regulates Th2 differentiation, making it an attractive target for atopic dermatitis (AD). The reported phosphopeptide-based STAT6 proteolysis-targeting chimera (PROTAC) established proof of concept for targeted STAT6 degradation, although its oral bioavailability and degradation potency remain suboptimal. Here, we report the discovery of orally active non-phosphopeptide STAT6 degraders. Among them, WW-210 exhibited picomolar DC50 values for STAT6 degradation and a more than 1000-fold degradation selectivity window over the other tested STAT family members. PK/PD studies demonstrated favorable oral exposure, measurable oral bioavailability, and effective STAT6 degradation in blood and spleen. In a mouse model of AD, WW-210 alleviated skin lesions, reduced serum IgE, restored filaggrin expression, and decreased mast cell infiltration. Collectively, WW-210 represents a potent, orally active STAT6 degrader with therapeutic potential for AD.