Tyrosine kinase 2 (TYK2) is a member of the JAK kinase family. Besides, it regulates signal transduction downstream of the IL-23/IL-12 pathway and the type I interferon family receptor, pairing with JAK2 or JAK1, respectively. Members of this family are key regulatory factors in the signal transduction pathways used by classical type I and type II immune cytokine receptors. Therefore, this family is a promising target for the treatment of various cytokine-dependent inflammations and immune diseases. Moreover, TYK2 is relevant to cytokines IL-23 and IL-12, as well as type I interferon (IFN α And IFN β), IL-6, and IL-10 families. Furthermore, the TYK2 signaling pathway is limited to specific immune pathways, which is different from other members of the JAK family. Meanwhile, JAK 1/2/3 are relevant to more extensive immunity (e.g., T cells and natural killer cells) and extra immune pathways (e.g., bone marrow effect, lipid metabolism).

Importantly, TYK2 is an essential enzyme that concentrates the input of cytokines that form immune responses. Nonetheless, TYK2 for IFN- α Signal transduction is crucial as human cells lacking Tyk2 are sensitive to IFN- α no response. In addition, TYK2 signaling is relevant to the immune system’s response to the IL-10 cytokine family. Now, we will introduce a highly selective, orally bioavailable allosteric TYK2 inhibitor, Deucravacitinib.

Deucravacitinib is an Orally Active TYK2 Allosteric Inhibitor for Autoimmune Diseases Research.

Firstly, Deucravacitinib (BMS-986165) is a highly selective, orally bioavailable allosteric TYK2 inhibitor for the treatment of autoimmune diseases. Particularly, Deucravacitinib selectively binds to the TYK2 pseudokinase (JH2) domain (IC₅₀=1.0 nM). Obviously, Deucravacitinib blocks receptor-mediated Tyk2 activation by stabilizing the regulatory JH2 domain. Deucravacitinib inhibits IL-12/23 and type I IFN pathways.

Secondly, Deucravacitinib selectively binds to the pseudokinase (JH2) domain of TYK2 and inhibits its function through an allosteric mechanism. Interestingly, Deucravacitinib maintains excellent potency in human and mouse whole blood (IC₅₀s=13 and 100 nM, respectively). Additionally, Deucravacitinib shows no significant hERG inhibition in the flux assay (IC₅₀>80 μM).

Finally, Deucravacitinib (BMS-986165) is a highly selective, orally bioavailable allosteric TYK2 inhibitor.

References:

[1] Wrobleski ST, et al. J Med Chem. 2019 Jul 18.