Understanding the Mechanism of Action in JAK Inhibitors

Jason Hawkes, MD, MS, medical dermatologist in Sacramento, California presented an in-depth overview on the mechanism of action (MOA) of Janus Kinase (JAK) inhibitors, a class of small molecules used to treat various inflammatory and autoimmune conditions. His 2024 Fall Clinical for PAs and NPs discussion encompassed the fundamental aspects of JAK inhibitors, their specific mechanisms, and their therapeutic applications.¹

Hawkes explained that the JAK-STAT pathway is a crucial signaling mechanism that mediates responses to various cytokines and growth factors, thereby playing a pivotal role in immune regulation. He emphasized that JAK inhibitors target the intracellular components of this pathway, disrupting the signaling and consequently modulating the immune response.

Hawkes detailed the 4 members of the JAK family: JAK1, JAK2, JAK3, and TYK2. Each of these kinases is associated with different cytokine receptors and biological functions. For instance, JAK1 is more selective for conditions like atopic dermatitis (AD), alopecia areata (AA), rheumatoid arthritis (RA), and others, while TYK2 is highly selective for psoriasis and potentially psoriatic arthritis.²

The redundancy in JAK enzymes means that blocking one can have wide-ranging effects on the immune system. This broad impact makes JAK inhibitors potent tools for managing autoimmune diseases, but also necessitates careful consideration of their side effects and safety profiles.One of the notable points of Hawkes' presentation was the discussion on the structural differences and similarities among JAK inhibitors. For example, JAK1/2/3 inhibitors often block the active site, while TYK2 inhibitors work through allosteric inhibition. A notable example is ritlecitinib, which selectively inhibits JAK3 through irreversible covalent binding to a specific cysteine residue (Cys-909).³

Hawkes also provided an overview of currently available JAK inhibitors and those in development. Among the oral JAK inhibitors are upadacitinib (JAK1), tofacitinib (JAK1/2/3 > TYK2), baricitinib (JAK1/2), abrocitinib (JAK1), ritlecitinib (JAK3/TEC), and deucravacitinib (TYK2). Topical JAK inhibitors include tofacitinib, ruxolitinib (JAK1/2), and delgocitinib (pan-JAK).^4-5

The safety profiles of JAK inhibitors vary significantly. For instance, TYK2 inhibitors tend to have lower incidences of acne/folliculitis and herpes infections compared to JAK1/2 inhibitors. The risk of thrombosis also differs across the JAK inhibitors, with JAK1/2 inhibitors having a higher association compared to TYK2 inhibitors. Hawkes highlighted the importance of regular monitoring for adverse events such as infections, thrombotic events, and changes in blood counts and lipid levels.

In his key takeaways, Hawkes stressed that the JAK-STAT pathway links extracellular signals to intracellular responses, making it essential for immune system regulation. The specificity of biologics does not equate to the selectivity seen with JAK inhibitors. TYK2 inhibitors should be distinguished from general JAK1/2/3 inhibitors due to their unique MOA and safety profiles. Clinicians should also be vigilant about the class-specific adverse events such as acne/folliculitis and herpes infections.

References

1. Hawkes J. Mechanism of action of JAKs. Presented at: 2024 Fall Clinical Dermatology Conference for PAs and NPs; May 31-June 2, 2024; Scottsdale, AZ.
2. Shawky AM, Almalki FA, Abdalla AN, Abdelazeem AH, Gouda AM. A comprehensive overview of globally approved JAK inhibitors. Pharmaceutics. 2022;14(5):1001. Published 2022 May 6. doi:10.3390/pharmaceutics14051001
3. Gerstenberger BS, Ambler C, Arnold EP, et al. Discovery of tyrosine kinase 2 (TYK2) inhibitor (PF-06826647) for the treatment of autoimmune diseases. J Med Chem. 2020;63(22):13561-13577. doi:10.1021/acs.jmedchem.0c00948
4. Dai Z, Chen J, Chang Y, Christiano AM. Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata. JCI Insight. 2021;6(7):e142205. Published 2021 Apr 8. doi:10.1172/jci.insight.142205
5. Ishizaki M, Akimoto T, Muromoto R, et al. Involvement of tyrosine kinase-2 in both the IL-12/Th1 and IL-23/Th17 axes in vivo. J Immunol. 2011;187(1):181-189. doi:10.4049/jimmunol.1003244