From the Guidelines
Upadacitinib is a JAK1 inhibitor with effects on JAK2.
JAK Receptors Blocked by Upadacitinib
- JAK1: Upadacitinib is a selective inhibitor of JAK1, which is involved in the signaling of various cytokines, including IL-6, IL-12, and IL-23.
- JAK2: Upadacitinib also has effects on JAK2, although to a lesser extent than JAK1. JAK2 is involved in the signaling of cytokines such as EPO and thrombopoietin.
Mechanism of Action
Upadacitinib works by reversibly inhibiting the kinase activity of JAK1 and JAK2, which prevents the phosphorylation of STATs and subsequent gene activation 1. This leads to a decrease in inflammation and immune response.
Comparison to Other JAK Inhibitors
Upadacitinib has a different selectivity profile compared to other JAK inhibitors, such as tofacitinib and baricitinib. Tofacitinib is a pan-JAK inhibitor, while baricitinib is a JAK1 and JAK2 inhibitor 1.
Clinical Implications
The selective inhibition of JAK1 by upadacitinib may result in a different safety profile compared to other JAK inhibitors. For example, upadacitinib may have a lower risk of anemia due to its reduced inhibition of JAK2, which is involved in EPO signaling 1. However, further research is needed to fully understand the clinical implications of upadacitinib's selectivity profile.
From the FDA Drug Label
Upadacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression. Upadacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through their pairing (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/JAK2, JAK2/TYK2). In a cell-free isolated enzyme assay, upadacitinib had greater inhibitory potency at JAK1 and JAK2 relative to JAK3 and TYK2.
Upadacitinib blocks the following JAK receptors:
- JAK1: with greater inhibitory potency
- JAK2: with greater inhibitory potency
- JAK3: with less inhibitory potency compared to JAK1 and JAK2
- TYK2: with less inhibitory potency compared to JAK1 and JAK2 It does not specifically block tyrosine kinase receptors, but rather the JAK enzymes. 2
From the Research
JAK Receptors Blocked by Upadacitinib
- Upadacitinib is a selective Janus kinase (JAK) inhibitor that more potently inhibits JAK1 than other JAK isoforms 3, 4
- The JAK receptors blocked by Upadacitinib include:
- JAK1: Upadacitinib has increased selectivity for JAK1 over other JAK isoforms 4
- JAK2: Upadacitinib has less selectivity for JAK2 compared to JAK1 4
- JAK3: Upadacitinib has less selectivity for JAK3 compared to JAK1 4
- Tyrosine kinase 2 (TYK2): Upadacitinib has less selectivity for TYK2 compared to JAK1 4, 5, 6, 7
Mechanism of Action
- Upadacitinib inhibits phosphorylation of downstream effector proteins, which consequently inhibits cytokine signaling for key pathways involved in inflammatory diseases 3
- The JAK-STAT (Janus kinase-signal transducers and activators of transcription) pathway is involved in the pathogenesis of several chronic and progressive immune-mediated inflammatory diseases 3, 5, 6, 7