TYK2 Inhibition Finally Comes of Age

Tyrosine kinase 2 (TYK2) was the first of the Janus family of non-receptor tyrosine kinases to be discovered. For three decades, the other members of this family, JAK1, JAK2, and JAK3, have dominated the research for inhibitors of autoimmune disease, largely because the effect upon them was more pronounced. They are called “Janus kinases” because they usually assemble and are activated in particular heterodimeric pairings, binding to the intracellular domains of specific cytokine receptors. Once active, a given JAK pair initiates several rounds of phosphorylation, resulting in the recruitment of a specific signal transducer and activator of transcription factors (STATs). Upon STAT phosphorylation, these particular STATs are sent to the nucleus to regulate genes involved in specific immune or hematopoietic responses.¹

While inflammatory cytokine signaling is essential in fighting off bacterial, fungal, or viral infection, it is usually transient and only sufficient to ward off the invaders. The T helper 17 branches of the immune system act by issuing pro-inflammatory cytokine messengers and are critical to fighting off pathogens. In fact, loss of function mutations in TYK2 has been found to leave patients wide open to viral and mycobacterial infections. However, when such signaling becomes constitutive, autoimmune diseases can arise. TYK2 involvement in excessive JAK signaling is associated with psoriasis, psoriatic arthritis, Crohn’s disease, axial spondyloarthritis, and systemic lupus erythematosus. In psoriasis, IL-17 produced by TYK2/JAK2 signaling in mature Th17 cells provokes target tissues to release IL-23, and this IL-23 returns to re-stimulate the same T-cell signaling in a vicious cycle of inflammation. Similarly, TYK2/JAK2 signaling in Th1 cells is stimulated by IL-12 binding, initiating a cell-mediated response. Interferon-alpha and beta binding initiate TYK2/JAK1 assembly and signal transduction.²

TYK2 Specific Inhibitors

Since phosphorylation, instigated by the given JAK pair, is required to send STATs to the nucleus, inhibition of ATP binding was the first target sought to abrogate signaling in the JAK-STAT system. The first such inhibitor, Tofacitinib, was discovered at the NIH and developed by Pfizer. It competes for attachment at the JAK ATP binding site, preventing JAK-mediated phosphorylation. This is all well and good. However, since this ATP binding site is common to all the JAKs, depending on concentration, various JAK inhibitors affected all the JAKS. While, for instance, rheumatoid arthritic symptoms could be dampened, other side effects often interfered with continuous treatment.³

Over time, ever more precise modifications have been made to inhibit only TYK2 specifically. However, one of the unfortunate impediments to developing specific TYK2 inhibitors was the slight molecular difference between the TYK2 ATP binding site in all preclinical test species and in humans. This produced a distorted view of the potency of various inhibitors until it was characterized and modified by Brian Gerstenberger’s group at Pfizer.⁴ With this knowledge in hand, his group, has produced a highly selective TYK2 ATP binding site inhibitor (PF06826647) that promises to deter autoimmune disease with exquisite precision.⁵ The Wrobleski group at Bristol-Myers Squibb has produced an inhibitor (BMS-986165) that binds the adjacent (pseudokinase) motif in TYK2, resulting in novel allosteric interference with ATP binding. This particular inhibitor is over 10,000 times more sensitive for TYK2 than any other JAK.⁶

Hopefully, these recent exciting developments will, at last, deliver on the promise of precise TYK2 targeted therapy for autoimmune disease.

References

1. Hromadova, D. et al. (2021) From Science to Success? Targeting Tyrosine Kinase 2 in Spondyloarthritis and Related Chronic Inflammatory Diseases. Frontiers in Genetics, Review, 05 July 2021. https://doi.org/10.3389.fgene.2021.685280

2. Ghoreschi, K. et al. (2021) TYK2 inhibition and its potential in the treatment of chronic inflammatory immune diseases. Journal of the German Society of Dermatology, 19(10), 1409-1420. https://doi.org/10.1111/ddg.14585

3. Gonciarz, M. et al. (2021) TYK2 as a target in the treatment of autoimmune and inflammatory diseases. Immunotherapy, 13(13), Review. https://doi.org/10.2217/imt-2021-0096

4. Gerstenberger, B. et al. (2020) Demonstration of In Vitro to In Vivo Translation of a TYK2 Inhibitor That Shows Cross-Species Potency Differences. Nature Scientific Reports, 10, Article number: 8974
https://www.nature.com/articles/s41598-020-65762-y

5. Gerstenberger, B. et al. (2020) Discovery of Tyrosine Kinase 2 (TYK2) Inhibitor (PF-06826647) for the Treatment of Autoimmune Diseases. Journal of Medicinal Chemistry, 63(22), 13561-13577.
https://doi.org/10.1021/acs.jmedchem.0c00948

6. Wrobleski, S. et al. (2019) Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor BMS-986165. Journal of Medicinal Chemistry, 62(20), 8973-8995. https://doi.org/10.1021/acs.jmedchem.9b00444