Janus kinase inhibitor

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A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, [1] is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

Contents

JAK inhibitors are used in the treatment of some cancers 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]

Contraindications

JAK enzymes are part of the JAK/STAT pathway. This signaling pathway transmits chemical signals from the outside of cells, specifically lymphocytes, and into the cell nucleus. 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. JAK3 inhibitors necessarily cause a loss or total absence of T cells and natural killer cells while leaving a normal amount of B cells. The loss of these essential lymphocytes cause a person to become highly susceptible to infection; moreover, usually JAK3 inhibitors are used by people with an autoimmune disease, who are already at a greater risk for infectioninfection. [6]

The US Food and Drug Administration (FDA) requires a boxed warning for the JAK inhibitors tofacitinib, baricitinib, and upadacitinib to warn about the risks of serious heart-related events, cancer, blood clots, and death. [7] [8]

The Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA) recommends that the Janus kinase inhibitors abrocitinib, filgotinib, baricitinib, upadacitinib, and tofacitinib should be used in the following people only if no suitable alternative treatments are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past, and those at increased risk of cancer. [9] [10] The committee also recommends using JAK inhibitors with caution in people with risk factors for blood clots in the lungs and in deep veins (venous thromboembolism (VTE)) other than those listed above. [9]

The special warnings by FDA and EMA are important for shared-decision making with the patient. [11]

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. [12]

The first JAK inhibitor to reach clinical trials was tofacitinib. Tofacitinib is a specific inhibitor of JAK3 (IC50 = 2 nM) thereby blocking the activity of IL-2, IL-4, IL-15 and IL-21. Hence Th2 cell differentiation is blocked and therefore tofacitinib is effective in treating allergic diseases. Tofacitinib to a lesser extent also inhibits JAK1 (IC50 = 100 nM) and JAK2 (IC50 = 20 nM), which in turn blocks 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. [13]

Some JAK1 inhibitors are based on a benzimidazole core. [14]

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. [15] [16] Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo[2,3-b]pyridine, as it mimics the pyrrolopyrimidine scaffold. [17] More information on the structure activity relationship of may be found in the article on JAK3 inhibitors.

Examples

Approved compounds

Drug Brand nameSelectivityApproval dateIndicationsReferences
Ruxolitinib (oral)Jakafi, JakaviJAK1, JAK2
  • November 2011 (US)
  • July 2012 (EU)
  • July 2014 (Japan)
 [18] [19]
Tofacitinib Xeljanz, Xeljanz XR, JaquinusJAK1, 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

 [20] [21]
Oclacitinib ApoquelJAK1May 2013 (US) [22] [23] [24]
Baricitinib OlumiantJAK1, JAK2
  • February 2017 (EU)
  • July 2017 (Japan)
  • May 2018 (US)
 [25] [26]
Peficitinib SmyrafJAK1, JAK3
  • March 2019 (Japan)
  • January 2020 (South Korea)
 [27] [28] [29]
Upadacitinib RinvoqJAK1
  • 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

 [30]
Fedratinib InrebicJAK2
  • August 2019 (US)
  • February 2021 (EU)
  • Primary and secondary myelofibrosis (intermediate-2 or high-risk)
 [31] [32]
Delgocitinib (topical)CorectimNon-selectiveJanuary 2020 (Japan) [33]
Filgotinib JyselecaJAK1September 2020 (EU, Japan)

Indicated in intolerance or inefficacy of DMARDs or conventional therapy

 [34]
Abrocitinib CibinqoJAK1
  • September 2021 (Japan)
  • December 2021 (EU)
  • January 2022 (US)
  • Refractory moderate-to-severe atopic dermatitis with inadequate response to other systemic therapy
 [35] [36] [37]
Ruxolitinib (topical)OpzeluraJAK1, JAK2September 2021 (US) [38]
Pacritinib VonjoJAK2February 2022 (US) [39]
Deucravacitinib Sotyktu TYK2 September 2022 (US) [40]
Ritlecitinib LitfuloJAK3June 2023 (US)
  • Severe alopecia areata
 [41]
Momelotinib OjjaaraJAK1, JAK2September 2023 (US)
  • Intermediate- or high-risk myelofibrosis in adults with anemia
 [42]

In clinical trials

Experimental drugs/indications

Related Research Articles

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

<span class="mw-page-title-main">Tyrosine kinase 2</span> Enzyme and coding gene in humans

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.

<span class="mw-page-title-main">Janus kinase 3</span> Mammalian protein found in Homo sapiens

Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the JAK3 gene.

<span class="mw-page-title-main">Tofacitinib</span> Medication

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. It is a janus kinase (JAK) inhibitor, discovered and developed by the National Institutes of Health and Pfizer.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

<span class="mw-page-title-main">Fedratinib</span> Chemical compound

Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.

<span class="mw-page-title-main">Momelotinib</span> Medication

Momelotinib, sold under the brand name Ojjaara, is an anticancer medication used for the treatment of myelofibrosis. It is a Janus kinase inhibitor and it is taken by mouth.

<span class="mw-page-title-main">Baricitinib</span> Chemical compound

Baricitinib, sold under the brand name Olumiant among others, is an immunomodulatory medication used for the treatment of rheumatoid arthritis, alopecia areata, and COVID-19. It acts as an inhibitor of janus kinase (JAK), blocking the subtypes JAK1 and JAK2.

<span class="mw-page-title-main">Filgotinib</span> Chemical compound

Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). It was developed by the Belgian-Dutch biotech company Galapagos NV.

<span class="mw-page-title-main">Oclacitinib</span> Medication

Oclacitinib, sold under the brand name Apoquel among others, is a veterinary medication used in the control of atopic dermatitis and pruritus from allergic dermatitis in dogs at least 12 months of age. Chemically, it is a synthetic cyclohexylamino pyrrolopyrimidine janus kinase inhibitor that is relatively selective for JAK1. It inhibits signal transduction when the JAK is activated and thus helps downregulate expression of inflammatory cytokines.

<span class="mw-page-title-main">Upadacitinib</span> Chemical compound (medication)

Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.

<span class="mw-page-title-main">Janus kinase 3 inhibitor</span>

Janus kinase 3 inhibitors, also called JAK3 inhibitors, are a new class of immunomodulatory agents that inhibit Janus kinase 3. They are used for the treatment of autoimmune diseases. The Janus kinases are a family of four nonreceptor tyrosine-protein kinases, JAK1, JAK2, JAK3, and TYK2. They signal via the JAK/STAT pathway, which is important in regulating the immune system. Expression of JAK3 is largely restricted to lymphocytes, while the others are ubiquitously expressed, so selective targeting of JAK3 over the other JAK isozymes is attractive as a possible treatment of autoimmune diseases.

<span class="mw-page-title-main">Decernotinib</span> Chemical compound

Decernotinib is an inhibitor of Janus kinase 3 (JAK3) discovered through a process of inhouse screening of a chemical compound library. Decernotinib also had the name VX-509 in development phase. It is an experimental drug with high selectivity for JAK3, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). It has been studied in clinical trials at Vertex Pharmaceuticals, and while it was not approved for clinical use it continues to be used for research.

<span class="mw-page-title-main">Cerdulatinib</span> Chemical compound

Cerdulatinib is a small molecule SYK/JAK kinase inhibitor in development for treatment of hematological malignancies. It has lowest nM IC50 values against TYK2, JAK1, JAK2, JAK3, FMS, and SYK.

<span class="mw-page-title-main">Abrocitinib</span> Chemical compound

Abrocitinib, sold under the brand name Cibinqo, is a medication used for the treatment of atopic dermatitis (eczema). It is a Janus kinase inhibitor and it was developed by Pfizer. It is taken by mouth.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

<span class="mw-page-title-main">Z583</span>

Z583 (GLXC-26150) is a chemical compound which acts as a potent and highly selective inhibitor of JAK3, and was developed for the treatment of rheumatoid arthritis.

<span class="mw-page-title-main">Izencitinib</span>

Izencitinib (TD-1473) is a drug which acts as a pan-Janus kinase inhibitor, binding with high affinity at all three subtypes JAK1, JAK2 and JAK3. It is taken orally and was developed to be gut selective with minimal absorption into the rest of the body, allowing targeting of inflammatory bowel disease but with reduced side effects compared to other similar drugs.

<span class="mw-page-title-main">Gusacitinib</span>

Gusacitinib (ASN002) is an investigational drug which acts as a pan-Janus kinase inhibitor, binding with similar affinity at JAK1, JAK2, JAK3 and TYK2, and also inhibiting spleen tyrosine kinase (SYK). It is taken orally and was developed for the treatment of eczema and dermatitis.

References

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  2. ↑ Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ (June 2008). "Therapeutic targeting of Janus kinases". Immunological Reviews. 223: 132–42. doi:10.1111/j.1600-065X.2008.00644.x. PMC   2634846 . PMID   18613833.
  3. ↑ Norman P (August 2014). "Selective JAK inhibitors in development for rheumatoid arthritis". Expert Opinion on Investigational Drugs. 23 (8): 1067–77. doi:10.1517/13543784.2014.918604. PMID   24818516. S2CID   21143324.
  4. 1 2 "JAK Inhibitors Showing Promise for Many Skin Problems - Conditions ranging from alopecia to vitiligo". 6 July 2017. Archived from the original on 13 July 2017. Retrieved 9 July 2017.
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