Discovery of a Highly Potent and Selective Tyrosine Kinase 2 (TYK2) Degrader with In Vivo Therapeutic Efficacy in a Murine Psoriasis 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 15t as an exceptionally potent and selective Tyk2 degrader with a DC₅₀ value of 0.42 nM and a D_max value of 95%, which potently and selectively blocked TYK2-dependent signaling. Importantly, 15t 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.