Janus kinase inhibitor

Source: Wikipedia, the free encyclopedia.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib,

TYK2), thereby interfering with the JAK-STAT signaling pathway
in lymphocytes.

It is used in the treatment of cancer and

inflammatory diseases[1][2] such as rheumatoid arthritis[3] and various skin conditions.[4] A Janus kinase 3 inhibitor is attractive as a possible treatment of various autoimmune diseases since its function is mainly restricted to lymphocytes. JAK inhibitors can suppress the signaling of pro-inflammatory cytokines. Pro-inflammatory cytokines are major contributors to the cause of an over active immune system, resulting in inflammation and pain. JAK inhibitors have the ability to slow down this over activity by the suppression of the intracellular signaling.[5] As of 2017, development of a selective JAK3 inhibitor was ongoing.[6] As of 2022, a JAK3 selective inhibitor, Z583 was developed. JAK3 only regulates certain gamma c cytokines, and Z583 completely inhibited gamma c signaling and blocked the development of inflammatory response.[7]

Contraindications

JAK3 is an enzyme in the body that is apart of the JAK/STAT pathway. This signaling pathway transmits chemical signals from the outside of cells, specifically lymphocytes, and into the nucleus of these cells. Signals relayed by JAK3 aid in the maturation and regulation of growth of T cells and natural killer cells. While this process is important, it can have negative side effects in the body as well for reasons that remain mostly unknown. In some people, JAK3 and the STAT pathway can cause synovial inflammation, joint destruction, and autoantibody production. By using a JAK3 inhibitor, there inevitably becomes a loss of JAK3 protein which in turn causes a loss or total absence of T cells, natural killer cells, and a normal amount of B cells. The loss of these essential lymphocytes cause a person to become highly susceptible to infection, however usually the inhibitor is only used by people with an autoimmune disease and are already at a greater risk for infection.[8]

The US Food and Drug Administration (FDA) requires a boxed warning for tofacitinib, baricitinib, and upadacitinib to include information about the risks of serious heart-related events, cancer, blood clots, and death.[9][10]

The Pharmacovigilance Risk Assessment Committee of the

venous thromboembolism (VTE)) other than those listed above.[11]

The special warnings by FDA and EMA are important for shared-decision making with the patient.[13]

Mechanism of action

Janus kinase inhibitors can be classed in several overlapping classes: they are

immunomodulators, they are DMARDs (disease-modifying antirheumatic drugs), and they are a subclass of tyrosine kinase inhibitors. They work by modifying the immune system via cytokine
activity inhibition.

Cytokines play key roles in controlling cell growth and the immune response. Many cytokines function by binding to and activating type I cytokine receptors and type II cytokine receptors. These receptors in turn rely on the Janus kinase (JAK) family of enzymes for signal transduction. Hence drugs that inhibit the activity of these Janus kinases block cytokine signaling.[1] JAKs relay signals from more than fifty cytokines, which is what makes them attractive therapeutic targets for autoimmune diseases.

More specifically, Janus kinases

phosphorylate activated cytokine receptors. These phosphorylated receptors in turn recruit STAT transcription factors which modulate gene transcription.[14]

The first JAK inhibitor to reach clinical trials was

IFN-γ and IL-6 signalling and consequently Th1 cell differentiation.[1]

One mechanism (relevant to psoriasis) is that the blocking of Jak-dependent IL-23 reduces IL-17 and the damage it causes.[4]

Molecule design

In September 2021, the U.S. Food and Drug Administration (FDA) approved the first JAK inhibitor, ruxolitinib, to treat a skin condition.[15]

Some JAK1 inhibitors are based on a benzimidazole core.[16]

JAK3 inhibitors target the catalytic ATP-binding site of JAK3 and various moieties have been used to get a stronger affinity and selectivity to the ATP-binding pockets. The base that is often seen in compounds with selectivity for JAK3 is pyrrolopyrimidine, as it binds to the same region of the JAKs as purine of the ATP binds.[17][18] Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo[2,3-b]pyridine, as it mimics the pyrrolopyrimidine scaffold.[19] More information on the structure activity relationship of may be found in the article on JAK3 inhibitors.

Examples

Approved compounds

Drug Brand name Selectivity Approval date Indications References
Ruxolitinib (oral) Jakafi, Jakavi JAK1, JAK2
  • November 2011 (US)
  • July 2012 (EU)
  • July 2014 (Japan)
  • Primary and secondary
    myelofibrosis
    (intermediate or high-risk)
  • hydroxyurea
  • Steroid-refractory acute GVHD
  • Chronic GVHD (second or third-line therapy)
[20][21]
Tofacitinib Xeljanz, Xeljanz XR, Jaquinus JAK1, JAK2, JAK3
  • November 2012 (US)
  • March 2013 (Japan)
  • March 2017 (EU)

Indicated in intolerance or inefficacy of TNF inhibitors or DMARDs, or other conventional therapy or biologic agents

[22][23]
Oclacitinib Apoquel JAK1 May 2013 (US) [24][25][26]
Baricitinib Olumiant JAK1, JAK2
  • February 2017 (EU)
  • July 2017 (Japan)
  • May 2018 (US)
[27][28]
Peficitinib Smyraf JAK1, JAK3
  • March 2019 (Japan)
  • January 2020 (South Korea)
[29][30][31]
Upadacitinib Rinvoq JAK1
  • August 2019 (US)
  • November 2019 (Japan)
  • December 2019 (EU)

Indicated in intolerance or inefficacy of TNF inhibitors or DMARDs, or other conventional therapy or biologic agents

[32]
Fedratinib Inrebic JAK2
  • August 2019 (US)
  • February 2021 (EU)
  • Primary and secondary
    myelofibrosis
    (intermediate-2 or high-risk)
[33][34]
Delgocitinib (topical) Corectim Non-selective January 2020 (Japan) [35]
Filgotinib Jyseleca JAK1 September 2020 (EU, Japan)

Indicated in intolerance or inefficacy of DMARDs or conventional therapy

[36]
Abrocitinib Cibinqo JAK1
  • September 2021 (Japan)
  • December 2021 (EU)
  • January 2022 (US)
  • Refractory moderate-to-severe atopic dermatitis with inadequate response to other systemic therapy
[37][38][39]
Ruxolitinib (topical) Opzelura JAK1, JAK2 September 2021 (US) [40]
Pacritinib Vonjo JAK2 February 2022 (US)
  • Primary and secondary
    myelofibrosis (intermediate or high-risk) with thrombocytopenia
[41]
Deucravacitinib Sotyktu TYK2 September 2022 (US) [42]
Ritlecitinib Litfulo JAK3 June 2023 (US)
  • Severe alopecia areata
[43]
Momelotinib Ojjaara JAK1, JAK2 September 2023 (US)
  • Intermediate- or high-risk myelofibrosis in adults with anemia
[44]

In clinical trials

Experimental drugs/indications

References

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