Janus kinase inhibitor explained

Atc Prefix:L04AF
Mode Of Action:Anti-inflammatory/
immunosuppressant
Mechanism Of Action:Enzyme inhibitor
Biological Target:Janus kinase

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.

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.

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

Brand name Selectivity Approval date Indications References
Ruxolitinib (oral) Jakafi, Jakavi JAK1, JAK2 [18] [19]
Xeljanz, Xeljanz XR, Jaquinus JAK1, JAK2, JAK3

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

[20] [21]
Apoquel JAK1 May 2013 (US) [22] [23] [24]
Olumiant JAK1, JAK2 [25] [26]
Smyraf JAK1, JAK3 [27] [28] [29]
Rinvoq JAK1

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

[30]
Inrebic JAK2
  • Primary and secondary myelofibrosis (intermediate-2 or high-risk)
[31] [32]
Delgocitinib (topical) Corectim Non-selective January 2020 (Japan) [33]
Jyseleca JAK1 September 2020 (EU, Japan)

Indicated in intolerance or inefficacy of DMARDs or conventional therapy

[34]
Cibinqo JAK1
  • Refractory moderate-to-severe atopic dermatitis with inadequate response to other systemic therapy
[35] [36] [37]
Ruxolitinib (topical) Opzelura JAK1, JAK2 September 2021 (US) [38]
Vonjo JAK2 February 2022 (US) [39]
Sotyktu September 2022 (US) [40]
Litfulo JAK3 June 2023 (US)
  • Severe alopecia areata
[41]
Ojjaara JAK1, JAK2 September 2023 (US)
  • Intermediate- or high-risk myelofibrosis in adults with anemia
[42]

In clinical trials

Experimental drugs/indications

Notes and References

  1. Kontzias A, Kotlyar A, Laurence A, Changelian P, O'Shea JJ . Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease . Current Opinion in Pharmacology . 12 . 4 . 464–70 . August 2012 . 22819198 . 3419278 . 10.1016/j.coph.2012.06.008 .
  2. Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ . Therapeutic targeting of Janus kinases . Immunological Reviews . 223 . 132–42 . June 2008 . 18613833 . 2634846 . 10.1111/j.1600-065X.2008.00644.x .
  3. Norman P . Selective JAK inhibitors in development for rheumatoid arthritis . Expert Opinion on Investigational Drugs . 23 . 8 . 1067–77 . August 2014 . 24818516 . 10.1517/13543784.2014.918604 . 21143324 .
  4. Web site: JAK Inhibitors Showing Promise for Many Skin Problems - Conditions ranging from alopecia to vitiligo . 6 July 2017 . 9 July 2017 . 13 July 2017 . https://web.archive.org/web/20170713140943/https://www.medpagetoday.com/Dermatology/GeneralDermatology/66485 . live .
  5. Web site: Tanaka Y, Luo Y, O'Shea JJ, Nakayamada S . January 5, 2022 . Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach . March 9, 2024 . Nature Reviews.
  6. Web site: August 1, 2017 . JAK3-deficient severe combined immunodeficiency . May 6, 2024 . Medline Plus.
  7. Web site: Janus Kinase (JAK) inhibitors: Drug Safety Communication - FDA Requires Warnings about Increased Risk of Serious Heart-related Events, Cancer, Blood Clots, and Death . U.S. Food and Drug Administration (FDA) . 2 September 2021 . 28 October 2022 . 28 October 2022 . https://web.archive.org/web/20221028203928/https://www.fda.gov/safety/medical-product-safety-information/janus-kinase-jak-inhibitors-drug-safety-communication-fda-requires-warnings-about-increased-risk . live .
  8. Web site: FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions . U.S. Food and Drug Administration (FDA) . 6 December 2021 . 28 October 2022 . 28 October 2022 . https://web.archive.org/web/20221028205749/https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death . live .
  9. EMA recommends measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders . European Medicines Agency (EMA) . 28 October 2022 . 28 October 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  10. Web site: Janus Kinase inhibitors (JAKi) . European Medicines Agency (EMA) . 28 October 2022 . 28 October 2022 . 28 October 2022 . https://web.archive.org/web/20221028143320/https://www.ema.europa.eu/en/medicines/human/referrals/janus-kinase-inhibitors-jaki . live .
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  13. Web site: JAK inhibitors: What your dermatologist wants you to know . 2023-07-30 . www.aad.org . en.
  14. 10.1021/acs.jmedchem.5b01263 . 26351728 . 58 . 18 . Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors . 2015 . Journal of Medicinal Chemistry . 7596–7602 . Kyoung Kim M, Shin H, Kwang-su P, Kim H, Park J, Kim K, Nam J, Choo H, Chong Y.
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  17. Web site: Synthesis and Evaluation of 1 H -Pyrrolo[2,3- b ]pyridine Derivatives as Novel Immunomodulators Targeting Janus Kinase 3 (PDF Download Available)]. 26 September 2017. ResearchGate.
  18. Vaddi K, Sarlis NJ, Gupta V . Ruxolitinib, an oral JAK1 and JAK2 inhibitor, in myelofibrosis . Expert Opinion on Pharmacotherapy . 13 . 16 . 2397–407 . November 2012 . 23051187 . 10.1517/14656566.2012.732998 . 29293800 .
  19. Web site: Jakafi (ruxolitinib) Tablets, for Oral Use. Full Prescribing Information . Incyte Corporation . 16 July 2016 . 2 April 2016 . https://web.archive.org/web/20160402162858/https://www.jakafi.com/pdf/prescribing-information.pdf . live .
  20. Zerbini CA, Lomonte AB . Tofacitinib for the treatment of rheumatoid arthritis . Expert Review of Clinical Immunology . 8 . 4 . 319–31 . May 2012 . 22607178 . 10.1586/eci.12.19 . 12226975 .
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  22. Gonzales AJ, Bowman JW, Fici GJ, Zhang M, Mann DW, Mitton-Fry M . Oclacitinib (Apoquel) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy . Journal of Veterinary Pharmacology and Therapeutics . 37 . 4 . 317–24 . August 2014 . 24495176 . 4265276 . 10.1111/jvp.12101 .
  23. FDA Approves Apoquel (oclacitinib tablet) to Control Itch and Inflammation in Allergic Dogs. Zoetis. 23 February 2017. 16 May 2013. 23 February 2017. https://web.archive.org/web/20170223215544/http://news.zoetis.com/press-release/companion-animals/fda-approves-apoquel-oclacitinib-tablet-control-itch-and-inflammatio. live.
  24. Web site: Apoquel- oclacitinib maleate tablet, coated . DailyMed . 28 July 2021 . 25 June 2023.
  25. Web site: FDA Approves Olumiant (baricitinib) 2-mg Tablets for the Treatment of Adults with Moderately-to-Severely Active Rheumatoid Arthritis . 1 June 2018 . . 21 August 2018 . 21 August 2018 . https://web.archive.org/web/20180821191940/https://investor.lilly.com/news-releases/news-release-details/fda-approves-olumiantr-baricitinib-2-mg-tablets-treatment-adults . live .
  26. FDA Approves First Systemic Treatment for Alopecia Areata . 13 June 2022 . U.S. Food and Drug Administration (FDA) . 10 August 2022.
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  30. AbbVie Receives FDA Approval of Rinvoq (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid Arthritis . AbbVie . 16 August 2019 .
  31. FDA approves treatment for patients with rare bone marrow disorder . U.S. Food and Drug Administration (FDA) . 16 August 2019 . 16 August 2019.
  32. U.S. FDA Approves Inrebic (Fedratinib) as First New Treatment in Nearly a Decade for Patients With Myelofibrosis . Celgene . Business Wire . 16 August 2019 . 25 June 2023.
  33. Dhillon S . Delgocitinib: First Approval . Drugs . 80 . 6 . 609–615 . April 2020 . 32166597 . 10.1007/s40265-020-01291-2 . 212681247 .
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