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.