Abstract Background STAT6 is a central transcription factor mediating IL-4/IL-13 signaling and plays a pivotal role in Type 2 immunity. Human STAT6 gain- or loss-of-function variants have been found to drive or protect against allergic diseases such as asthma and atopic dermatitis (AD). However, whether direct STAT6 degradation can achieve symptomatic relief in allergic diseases remains unclear. Methods and Results Using an AI-assisted, structure- and knowledge-based drug discovery platform, we successfully identified a series of PROTAC molecules that induced STAT6-cereblon (CRBN) complex formation with single-digit nanomolar EC50 values, as determined by a homogeneous time-resolved fluorescence ternary binding assay. X-ray crystallography revealed that the warhead interacted with the STAT6 SH2 domain at a site distinct from the IL-4Rα-binding pocket. The molecules triggered robust STAT6-HiBiT degradation and suppressed STAT6 reporter activity with IC50 values below 30 pM, exhibiting 5000-fold selectivity over other STAT family members. Functionally, the PROTAC molecules potently suppressed IL-4-induced TARC (CCL17) release from primary human peripheral blood mononuclear cells (IC50 30 pM), achieving or exceeding the potency of the IL-4Rα antibody dupilumab. Moreover, they also blocked IL-13-induced periostin release, a clinical biomarker and effector in Type 2 immunity-driven asthma, from human bronchial smooth muscle cells (IC50 50 pM). Consistent inhibition of IL-4-induced TARC release from mouse splenocytes, together with favorable DMPK properties, supports advancement to in vivo pharmacodynamic and efficacy studies via oral administration. Conclusions We have successfully identified a series of potent, selective, and orally bioavailable STAT6 degraders that effectively suppress IL-4 and IL-13 signaling. These molecules provide robust in vivo tools to explore whether STAT6 degradation can translate into symptomatic benefit in allergic disease models, and represent a promising oral therapeutic strategy for Type 2 inflammation. This abstract is funded by: None
Zhou et al. (Fri,) studied this question.