Discovery ofa Highly Potent and Selective TyrosineKinase 2 (TYK2) Degrader with In Vivo Therapeutic Efficacy in a MurinePsoriasis Model

Tyrosine kinase 2 (TYK2), a critical scaffolding kinase required for type I interferon, IL-12 and IL-23 cytokine signaling, represents a compelling therapeutic target for various autoimmune diseases. However, existing TYK2 inhibitors only modulate its kinase activity. Here, we report the development of a first series of CRBN-recruiting TYK2 PROTACs based on an allosteric TYK2 inhibitor. Optimization of the potency and metabolic stability identified <b>15t</b> as an exceptionally potent and selective TYK2 degrader with a DC₅₀ value of 0.42 nM and a <i>D</i>_max value of 95%, which potently and selectively blocked TYK2-dependent signaling. Importantly, <b>15t</b> was active in vivo and significantly suppressed TYK2-mediated pathology in a murine psoriasis model without apparent toxicity. Collectively, our study provides a potentially valuable chemical knockdown probe for subtype-selective TYK2 degradation and further understanding TYK2 scaffolding biology, demonstrating the therapeutic potential of TYK2 PROTACs in immuno-inflammatory diseases such as psoriasis.