Discovery of a Potent, Selective, and Orally Efficacious STAT6 PROTAC for the Treatment of Atopic Dermatitis.

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.