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 Dmax 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.