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.

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. As of 2017, development of a selective JAK3 inhibitor was ongoing.[5]

Contraindications

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.[6][7]

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.[8][9] 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.[8]

The special warnings by FDA and EMA are important for shared-decision making with the patient.[10]

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 signalling.[1]

More specifically, Janus kinases phosphorylate activated cytokine receptors. These phosphorylated receptors in turn recruit STAT transcription factors which modulate gene transcription.[11]

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.[12]

Some JAK1 inhibitors are based on a benzimidazole core.[13]

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.[14][15] Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo[2,3-b]pyridine, as it mimics the pyrrolopyrimidine scaffold.[16] 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)
[17][18]
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

[19][20]
Oclacitinib Apoquel JAK1 May 2013 (US) [21][22][23]
Baricitinib Olumiant JAK1, JAK2
  • February 2017 (EU)
  • July 2017 (Japan)
  • May 2018 (US)
[24][25]
Peficitinib Smyraf JAK1, JAK3
  • March 2019 (Japan)
  • January 2020 (South Korea)
[26][27][28]
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

[29]
Fedratinib Inrebic JAK2
  • August 2019 (US)
  • February 2021 (EU)
  • Primary and secondary myelofibrosis (intermediate-2 or high-risk)
[30][31]
Delgocitinib (topical) Corectim Non-selective January 2020 (Japan) [32]
Filgotinib Jyseleca JAK1 September 2020 (EU, Japan)

Indicated in intolerance or inefficacy of DMARDs or conventional therapy

[33]
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
[34][35][36]
Ruxolitinib (topical) Opzelura JAK1, JAK2 September 2021 (US) [37]
Pacritinib Vonjo JAK2 February 2022 (US) [38]
Deucravacitinib Sotyktu TYK2 September 2022 (US) [39]
Ritlecitinib Litfulo JAK3 June 2023 (US)
  • Severe alopecia areata
[40]
Momelotinib Ojjaara JAK1, JAK2 September 2023 (US)
  • Intermediate- or high-risk myelofibrosis in adults with anemia
[41]

In clinical trials

Experimental drugs/indications

References

  1. ^ a b c d Kontzias A, Kotlyar A, Laurence A, Changelian P, O'Shea JJ (August 2012). "Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease". Current Opinion in Pharmacology. 12 (4): 464–70. doi:10.1016/j.coph.2012.06.008. PMC 3419278. PMID 22819198.
  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. ^ a b "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.
  5. ^ Forster M, Gehringer M, Laufer SA (September 2017). "Recent advances in JAK3 inhibition: Isoform selectivity by covalent cysteine targeting". Bioorganic & Medicinal Chemistry Letters. 27 (18): 4229–4237. doi:10.1016/j.bmcl.2017.07.079. PMID 28844493.
  6. ^ "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. Archived from the original on 28 October 2022. Retrieved 28 October 2022.
  7. ^ "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. Archived from the original on 28 October 2022. Retrieved 28 October 2022.
  8. ^ a b "EMA recommends measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders". European Medicines Agency (EMA) (Press release). 28 October 2022. Retrieved 28 October 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  9. ^ "Janus Kinase inhibitors (JAKi)". European Medicines Agency (EMA). 28 October 2022. Archived from the original on 28 October 2022. Retrieved 28 October 2022.
  10. ^ Kragstrup TW, Glintborg B, Svensson AL, McMaster C, Robinson PC, Deleuran B, Liew DF (2022). "Waiting for JAK inhibitor safety data". RMD Open. 8 (1): e002236. doi:10.1136/rmdopen-2022-002236. PMC 8867353. PMID 35197363.
  11. ^ Furumoto Y, Gadina M (October 2013). "The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders". BioDrugs. 27 (5): 431–8. doi:10.1007/s40259-013-0040-7. PMC 3778139. PMID 23743669.
  12. ^ "JAK inhibitors: What your dermatologist wants you to know". www.aad.org. Retrieved 30 July 2023.
  13. ^ Kyoung Kim M, Shin H, Kwang-su P, Kim H, Park J, Kim K, Nam J, Choo H, Chong Y (2015). "Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors". Journal of Medicinal Chemistry. 58 (18): 7596–7602. doi:10.1021/acs.jmedchem.5b01263. PMID 26351728.
  14. ^ Clark JD, Flanagan ME, Telliez JB (June 2014). "Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases". Journal of Medicinal Chemistry. 57 (12): 5023–5038. doi:10.1021/jm401490p. PMID 24417533.
  15. ^ Tan L, Akahane K, McNally R, Reyskens KM, Ficarro SB, Liu S, et al. (August 2015). "Development of Selective Covalent Janus Kinase 3 Inhibitors". Journal of Medicinal Chemistry. 58 (16): 6589–6606. doi:10.1021/acs.jmedchem.5b00710. PMC 4777322. PMID 26258521.
  16. ^ "Synthesis and Evaluation of 1 H -Pyrrolo[2,3- b ]pyridine Derivatives as Novel Immunomodulators Targeting Janus Kinase 3 (PDF Download Available)". ResearchGate. Retrieved 26 September 2017.
  17. ^ Vaddi K, Sarlis NJ, Gupta V (November 2012). "Ruxolitinib, an oral JAK1 and JAK2 inhibitor, in myelofibrosis". Expert Opinion on Pharmacotherapy. 13 (16): 2397–407. doi:10.1517/14656566.2012.732998. PMID 23051187. S2CID 29293800.
  18. ^ "Jakafi (ruxolitinib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Incyte Corporation. Archived (PDF) from the original on 2 April 2016. Retrieved 16 July 2016.
  19. ^ Zerbini CA, Lomonte AB (May 2012). "Tofacitinib for the treatment of rheumatoid arthritis". Expert Review of Clinical Immunology. 8 (4): 319–31. doi:10.1586/eci.12.19. PMID 22607178. S2CID 12226975.
  20. ^ "Xeljanz (tofacitinib) Tablets, for Oral Use and Xeljanz XR (tofacitinib) Extended Release Tablets, for Oral Use. Full Prescribing Information". Pfizer Labs. Division of Pfizer, Inc. NY, NY 10017. Archived from the original on 14 April 2019. Retrieved 16 July 2016.
  21. ^ Gonzales AJ, Bowman JW, Fici GJ, Zhang M, Mann DW, Mitton-Fry M (August 2014). "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. doi:10.1111/jvp.12101. PMC 4265276. PMID 24495176.
  22. ^ "FDA Approves Apoquel (oclacitinib tablet) to Control Itch and Inflammation in Allergic Dogs" (Press release). Zoetis. 16 May 2013. Archived from the original on 23 February 2017. Retrieved 23 February 2017.
  23. ^ "Apoquel- oclacitinib maleate tablet, coated". DailyMed. 28 July 2021. Retrieved 25 June 2023.
  24. ^ "FDA Approves Olumiant (baricitinib) 2-mg Tablets for the Treatment of Adults with Moderately-to-Severely Active Rheumatoid Arthritis". Eli Lilly and Company. 1 June 2018. Archived from the original on 21 August 2018. Retrieved 21 August 2018.
  25. ^ "FDA Approves First Systemic Treatment for Alopecia Areata". U.S. Food and Drug Administration (FDA) (Press release). 13 June 2022. Retrieved 10 August 2022.
  26. ^ Kivitz AJ, Gutierrez-Ureña SR, Poiley J, Genovese MC, Kristy R, Shay K, Wang X, Garg JP, Zubrzycka-Sienkiewicz A (April 2017). "Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate". Arthritis & Rheumatology. 69 (4): 709–719. doi:10.1002/art.39955. PMID 27748083.
  27. ^ Genovese MC, Greenwald M, Codding C, Zubrzycka-Sienkiewicz A, Kivitz AJ, Wang A, Shay K, Wang X, Garg JP, Cardiel MH (May 2017). "Peficitinib, a JAK Inhibitor, in Combination With Limited Conventional Synthetic Disease-Modifying Antirheumatic Drugs in the Treatment of Moderate-to-Severe Rheumatoid Arthritis". Arthritis & Rheumatology. 69 (5): 932–942. doi:10.1002/art.40054. PMID 28118538.
  28. ^ Markham A, Keam SJ (June 2019). "Peficitinib: First Global Approval". Drugs. 79 (8): 887–891. doi:10.1007/s40265-019-01131-y. PMID 31093950. S2CID 155093525.
  29. ^ "AbbVie Receives FDA Approval of Rinvoq (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid Arthritis". AbbVie (Press release). Retrieved 16 August 2019.
  30. ^ "FDA approves treatment for patients with rare bone marrow disorder". U.S. Food and Drug Administration (FDA) (Press release). 16 August 2019. Retrieved 16 August 2019.
  31. ^ "U.S. FDA Approves Inrebic (Fedratinib) as First New Treatment in Nearly a Decade for Patients With Myelofibrosis" (Press release). Celgene. 16 August 2019. Retrieved 25 June 2023 – via Business Wire.
  32. ^ Dhillon S (April 2020). "Delgocitinib: First Approval". Drugs. 80 (6): 609–615. doi:10.1007/s40265-020-01291-2. PMID 32166597. S2CID 212681247.
  33. ^ "Clinical Trials with GLPG0634". ClinicalTrials.gov. Archived from the original on 18 October 2016. Retrieved 16 July 2016.
  34. ^ "Clinical Trials with PF04965842". ClinicalTrials.gov. Archived from the original on 31 August 2021. Retrieved 21 May 2017.
  35. ^ "Abrocitinib (PF-04965842)". MedChemExpress. Archived from the original on 19 March 2020. Retrieved 21 November 2019.
  36. ^ "Study to Evaluate Efficacy and Safety of PF-04965842 in Subjects Aged 12 Years And Older With Moderate to Severe Atopic Dermatitis (JADE Mono-1)". ClinicalTrials.gov. 20 November 2019. Archived from the original on 22 February 2020. Retrieved 21 November 2019.
  37. ^ "Opzelura (ruxolitinib) Cream, for Topical Use. Full Prescribing Information" (PDF). Incyte Corporation. Archived (PDF) from the original on 28 August 2022. Retrieved 10 September 2022.
  38. ^ "Vonjo (pacritinib) Capsules, for Oral Use. Full Prescribing Information" (PDF). CTI BioPharma Corp. Archived (PDF) from the original on 10 September 2022. Retrieved 10 September 2022.
  39. ^ "Sotyktu (deucravacitinib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Bristol-Myers Squibb Company. Archived (PDF) from the original on 10 September 2022. Retrieved 10 September 2022.
  40. ^ "Litfulo (ritlecitinib) Capsules, for Oral Use. Full Prescribing Information". Pfizer, Inc.
  41. ^ "Ojjaara (momelotinib) Tablets, for Oral Use. Full Prescribing Information". DailyMed. 15 September 2023. Retrieved 20 September 2023.
  42. ^ Liu D, Mamorska-Dyga A (July 2017). "Syk inhibitors in clinical development for hematological malignancies". Journal of Hematology & Oncology. 10 (1): 145. doi:10.1186/s13045-017-0512-1. PMC 5534090. PMID 28754125.
  43. ^ "Clinical trials with LY2784544 (Gandotinib)". ClinicalTrials.gov. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
  44. ^ Shabbir M, Stuart R (March 2010). "Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside". Expert Opinion on Investigational Drugs. 19 (3): 427–36. doi:10.1517/13543781003598862. PMID 20141349. S2CID 13558158.
  45. ^ "Momelotinib in Transfusion-Dependent Adults with Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF)". ClinicalTrials.gov. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
  46. ^ "Momelotinib Combined with Capecitabine and Oxaliplatin in Adults with Relapsed/Refractory Metastatic Pancreatic Ductal Adenocarcinoma". ClinicalTrials.gov. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
  47. ^ Hart S, Goh KC, Novotny-Diermayr V, Hu CY, Hentze H, Tan YC, et al. (November 2011). "SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies". Leukemia. 25 (11): 1751–9. doi:10.1038/leu.2011.148. PMID 21691275.
  48. ^ "Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis with Thrombocytopenia". ClinicalTrials.gov. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
  49. ^ "Pacritinib in Combination with Low Dose Decitabine in Intermediate-High Risk Myelofibrosis or Myeloproliferative Neoplasm (MPN)/Myelodysplastic Syndrome (MDS)". ClinicalTrials.gov. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
  50. ^ "BMS-986165 Phase 2, 3". ClinicalTrials.gov. Archived from the original on 12 April 2021. Retrieved 29 July 2020.
  51. ^ Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM (March 2003). "Discovery of JSI-124 (cucurbitacin I), a selective Janus kinase/signal transducer and activator of transcription 3 signaling pathway inhibitor with potent antitumor activity against human and murine cancer cells in mice". Cancer Research. 63 (6): 1270–9. PMID 12649187. Archived from the original on 17 September 2016. Retrieved 16 July 2016.
  52. ^ Meyer SC, Keller MD, Chiu S, Koppikar P, Guryanova OA, Rapaport F, et al. (July 2015). "CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms". Cancer Cell. 28 (1): 15–28. doi:10.1016/j.ccell.2015.06.006. PMC 4503933. PMID 26175413.
  53. ^ Stallard J (23 July 2015). "Discovery Could Boost New Therapies for Myeloproliferative Neoplasms". Memorial Sloan Kettering Cancer Center. Archived from the original on 16 June 2016. Retrieved 16 July 2016.
  54. ^ Gershon E (19 June 2014). "In Hairless Man, Arthritis Drug Spurs Hair Growth — Lots of It". Yale News. Archived from the original on 19 July 2016. Retrieved 16 July 2016.
  55. ^ Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, Clynes R, Christiano AM (October 2015). "Pharmacologic inhibition of JAK-STAT signaling promotes hair growth". Science Advances. 1 (9): e1500973. Bibcode:2015SciA....1E0973H. doi:10.1126/sciadv.1500973. PMC 4646834. PMID 26601320.