Tyk2 Targeting in Immune-Mediated Inflammatory Diseases

Abstract

The Janus kinase (Jak)/signal transducer and activating protein (STAT) pathways mediate the intracellular signaling of cytokines in a wide spectrum of cellular processes. They participate in physiologic and inflammatory cascades and have become a major focus of research, yielding novel therapies for immune-mediated inflammatory diseases (IMID). Genetic linkage has related dysfunction of Tyrosine kinase 2 (Tyk2)-the first member of the Jak family that was described-to protection from psoriasis. Furthermore, Tyk2 dysfunction has been related to IMID prevention, without increasing the risk of serious infections; thus, Tyk2 inhibition has been established as a promising therapeutic target, with multiple Tyk2 inhibitors under development. Most of them are orthosteric inhibitors, impeding adenosine triphosphate (ATP) binding to the JH1 catalytic domain-which is highly conserved across tyrosine kinases-and are not completely selective. Deucravacitinib is an allosteric inhibitor that binds to the pseudokinase JH2 (regulatory) domain of Tyk2; this unique mechanism determines greater selectivity and a reduced risk of adverse events. In September 2022, deucravacitinib became the first Tyk2 inhibitor approved for the treatment of moderate-to-severe psoriasis. A bright future can be expected for Tyk2 inhibitors, with newer drugs and more indications to come.

Keywords: inflammatory diseases; psoriasis; treatment.

Figure 1

Janus kinase-signal transducer and activator of transcription pathway. Cytokines bind to their receptor, leading to the activation of Jak and their phosphorylation. Subsequently, STAT is phosphorylated and dimerized. Activated STAT dimers translocate to the nucleus and regulate gene transcription and expression. Created with BioRender.com (accessed on 14 January 2023). Abbreviations: FERM, 4.1 ezrin, radixin moesin domain; SH2, Src-homology 2 domain; JH1, jak homology domain 1 (kinase domain); JH2, jak homology domain 2 (pseudokinase domain).

Figure 2

Cytokine signaling mediated by Jak-STAT. Each cytokine interacts with a particular combination of Jak-STAT molecules. Created with BioRender.com (accessed on 14 January 2023). Abbreviations: Jak, Janus kinase; STAT, signal transducer and activator of transcription; Tyk2, tyrosine kinase 2; IFN, interferon; IL, interleukin; EPO, erythropoietin; GH, growth hormone; TPO, thrombopoietin; GM-CSF, granulocyte macrophage colony-stimulating factor.

Figure 3

Tyk2 mediates signaling of IFN-α/β, IL-12, IL-23, IL-10, IL-22, and IL-6. Created with BioRender.com (accessed on 14 January 2023). Abbreviations: Tyk2, tyrosine kinase 2; IFN, interferon; IL, interleukin; Jak, Janus kinase; STAT, signal transducer and activator of transcription; Th, T-helper; R, Receptor.

Figure 4

Diagram of mechanism of action for the treatments for IMIDs. The receptor-blocking antibody binds to the receptor, preventing its capacity to bind to the cytokine. The. cytokine-blocking antibody binds to the cytokine, blocking its capacity to bind to the receptor. Jak inhibitors bind to the JH1 domain—kinase domain—impeding adenosine triphosphate (ATP) binding to the JH1 catalytic domain. Deucravacitinib and BMS-986202 bind to the JH2 domain, locking the regulatory (JH2) domain into an inhibitory contact with the catalytic domain (JH1). Created with BioRender.com (accessed on 14 January 2023). Abbreviations: FERM, 4.1 ezrin, radixin moesin domain; SH2, Src-homology 2 domain; JH1, jak homology domain 1 (kinase domain); JH2, jak homology domain 2 (pseudokinase domain).