Allosteric TYK2 inhibition: redefining autoimmune disease therapy beyond JAK1-3 inhibitors

Abstract

JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.

Keywords: Autoimmune disease; Deucravacitinib; JAK inhibitors; TYK2.

Fig. 1

The JAK-STAT proteins and pathway. (a) Homology and functional domain structure of JAKs. (b) The conserved domain structure of the seven STAT family members, with the SH2 domain determining the specificity for a particular receptor (c) Canonical JAK-STAT signal transduction. The binding of a ligand to its cognate receptor at the cell surface induces receptor oligomerization (i) and activation of two or more non-covalently associated JAKs through trans- and autophosphorylation (ii). The activated JAKs phosphorylate tyrosine residues in the receptors' intracellular domains creating docking sites for recruited STATs (iii). Once docked, phosphorylation by JAKs leads to a conformational change that allows STAT dimerization (iv). Activated STATs translocate to the nucleus, where they exert their activating or suppressing effect on gene expression (v). Abbreviations: FERM, four-point-one, ezrin, radixin, moesin; SH2, Src-homology 2; TAD, tyrosine activation domain.

Fig. 2

Crystal structures of the TYK2 JH1 kinase (left, PDB ID: 4GVJ), and TYK2 JH2 pseudokinase domains (right, PDB ID: 6NZP). The ATP binding site of JH1 is situated in the cleft between the N and C lobes connected by two regulatory spines. The N-terminal lobe comprises a five-stranded beta-sheet and an alpha-C helix crucial for kinase activation. A glycine-rich loop (purple) serves to bind ATP through hydrogen bond formation between the alpha-C helix and the ATP. The C-terminal lobe is mainly helical and contains an H-R-D motif of the catalytic loop (yellow), in which the aspartic acid acts as the catalytic base during phosphoryl transfer, and a D-F-G motif (green) in which the aspartic acid binds the Mg2+ that coordinates ATP. The phosphorylation of two adjacent tyrosine residues (turquoise) is a key step in JAK activation. The location of the natural variant P1104A is shown in pink. The TYK2 JH2 pseudokinase domain (right) has a canonical kinase fold and can bind ATP but lacks key catalytic residues (blue), harbouring instead T658 that cannot form a salt bridge between the αC-helix and β-strand3, P760 in the pseudokinase D-P-G motif and G733 and N734 that form the pseudokinase H-G-N motif. The JH2 structure is shown with deucravacitinib (red).

Fig. 3

Cytokines signal via combinations of JAKs. Currently, 12 JAK inhibitors are approved for the treatment of a variety of diseases (dark-shaded boxes) and investigated in phase 3 clinical trials (light-shaded boxes) for additional conditions. Abbreviations: MF, myelofibrosis; PV, polycythaemia vera; GVHD, graft versus host disease; AD, atopic dermatitis; VI, vitiligo; RA, rheumatoid arthritis; UC, ulcerative colitis; JIA, juvenile idiopathic arthritis; PSA, psoriatic arthritis; JPSA, juvenile psoriatic arthritis; AS, ankylosing spondylitis; PN, prurigo nodularis; PC, pancreatic cancer; HLH, haemophagocytic lymphohistiocytosis; ALL, acute lymphoblastic leukemia; AA, alopecia areata; PSO, psoriasis; TAK, Takayasu arteritis; GB, glioblastoma; GPA, granulomatosis with polyangiitis; DM, dermatomyositis; SSc, systemic sclerosis; SLE, systemic lupus erythematosus; UV, uveitis; P, pneumonia; Ecz, eczema; nr-axSpA, non-radiographic axial spondylitis; CD, Crohn’s disease; HS, hidradenitis suppurativa; GCA, giant cell arteritis; PP, palmoplantar postulosis; Sjogren’s syndrome.

Fig. 4

The TYK2 allosteric inhibitor deucravacitinib mimics the functional effect of the natural variant P1104A. (a) Ligand-receptor binding induces TYK2 activation. Currently licensed JAK1-3 type I inhibitors (green) target JH1 and work via ATP competition. (b) The natural variant P1104A stabilizes the inactive JH1 conformation. (c) The TYK2 allosteric inhibitor (shown by its molecular structure) binds to JH2, locking this regulatory domain into an inhibitory interaction with JH1, thereby preventing TYK2 activation and downstream signalling. Abbreviation: WT, wild-type allele.