Janus kinase inhibitor
Janus kinase inhibitors, also known as JAK inhibitors or jakinibs, are a type of medication that functions by inhibiting 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.
These inhibitors have therapeutic application in the treatment of cancer and inflammatory diseases such as rheumatoid arthritis. There is interest in their use for various skin conditions. JAK3 inhibitors are attractive as a possible treatment of various autoimmune diseases since its functions is mainly restricted to lymphocytes. Development for a selective JAK3 inhibitors are ongoing.
Mechanism of action
Cytokines play key roles in controlling cell growth and the immune response. Many cytokines function by binding to and activating type I 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.
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.
One mechanism (relevant to psoriasis) is that the blocking of Jak-dependent IL-23 reduces IL-17 and the damage it causes.
This section needs expansion. You can help by adding to it. (April 2016)
- Ruxolitinib (trade names Jakafi/Jakavi) against JAK1/JAK2 for psoriasis, myelofibrosis, and rheumatoid arthritis. Approved by the U.S. FDA in November 2011 for myelofibrosis (intermediate- or high-risk) and polycythemia vera, in patients with an inadequate response or intolerance to hydroxyurea.
- Tofacitinib (trade names Xeljanz/Jakvinus, formerly known as tasocitinib and CP-690550) against JAK3 for psoriasis and rheumatoid arthritis. U.S. FDA approved it in November 2012 for rheumatoid arthritis (moderately-to-severely active) in patients who had an inadequate response or intolerance to methotrexate.
- Oclacitinib (trade name Apoquel) — against JAK1 for the control of pruritus associated with allergic dermatitis and the control of atopic dermatitis in dogs at least 12 months of age.
- Baricitinib (trade name Olumiant) against JAK1/JAK2 for rheumatoid arthritis.
- Peficitinib (ASP015K, JNJ-54781532; trade name Smyraf) mainly inhibits JAK3 and used for treatment of rheumatoid arthritis. Approved for use in Japan in 2019.
- Fedratinib (SAR302503; trade name Inrebic) is a JAK2 inhibitor for treatment of primary myelofibrosis (including in patients those previously treated with ruxolitinib), or secondary myelofibrosis (post-polycythemia vera or post-essential thrombocythemia. Approved by U.S. FDA on 16 August 2019.
- Upadacitinib (trade name Rinvoq; ABT-494) against JAK1 for rheumatoid arthritis. Approved by U.S FDA on 16 August 2019.
In clinical trials
- Filgotinib (G-146034, GLPG-0634) against JAK1 for rheumatoid arthritis and Crohn's disease.
- Cerdulatinib (PRT062070) dual SYK/JAK inhibitor for hematological malignancies.
- Gandotinib (LY-2784544) against JAK2 for myeloproliferative neoplasms.
- Lestaurtinib (CEP-701) against JAK2 for acute myeloid leukemia (AML).
- Momelotinib (GS-0387, CYT-387) against JAK1 and JAK2 for myeloproliferative disorders and relapsed/refractory metastatic pancreatic cancer.
- Pacritinib (SB1518) against JAK2 for relapsed lymphoma and advanced myeloid malignancies, also myelofibrosis, myeloproliferative neoplasms and myelodysplastic syndrome.
- PF-04965842 against JAK1 for atopic dermatitis and moderate to severe psoriasis. Currently in phase II.
- Cucurbitacin I (JSI-124).
- CHZ868 — a type II JAK2 inhibitor for use in myeloproliferative disorders and chronic myelomonocytic leukemia (CMML).
- Tofacitinib for alopecia universalis.
- Topical tofacitinib and ruxolitinib for alopecia.
- Topical ruxolitinib for Vitiligo
- 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.
- 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.
- 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.
- "JAK Inhibitors Showing Promise for Many Skin Problems - Conditions ranging from alopecia to vitiligo". 6 July 2017.
- 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.
- 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.
- 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.
- 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.
- "Ruxolitinib (Jakafi) for myelofibrosis". The Medical Letter on Drugs and Therapeutics. 54 (1387): 27–8. April 2012. PMID 22469651.
- Ostojic A, Vrhovac R, Verstovsek S (November 2011). "Ruxolitinib for the treatment of myelofibrosis". Drugs of Today. 47 (11): 817–27. doi:10.1358/dot.2011.47.11.1708829. PMID 22146225.
- Mesa RA, Yasothan U, Kirkpatrick P (February 2012). "Ruxolitinib". Nature Reviews. Drug Discovery. 11 (2): 103–4. doi:10.1038/nrd3652. PMID 22293561.
- "Jakafi (ruxolitinib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Incyte Corporation. Wilmington, DE 19803. Retrieved 16 July 2016.
- 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.
- "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. Retrieved 16 July 2016.
- 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.
- "FDA Approves Apoquel (oclacitinib tablet) to Control Itch and Inflammation in Allergic Dogs". Zoetis. 16 May 2013. Retrieved 23 February 2017.
- "Apoquel (oclacitinib maleate tablet) Full Prescribing Information" (PDF). Zoetis Inc. Kalamazoo, MI 49007. Retrieved 23 February 2017.
- "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. Retrieved 21 August 2018.
- 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.
- 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.
- Markham A, Keam SJ (June 2019). "Peficitinib: First Global Approval". Drugs. 79 (8): 887–891. doi:10.1007/s40265-019-01131-y. PMID 31093950.
- "FDA approves treatment for patients with rare bone marrow disorder". FDA. 16 August 2019. Retrieved 16 August 2019.
- "U.S. FDA Approves INREBIC® (Fedratinib) as First New Treatment in Nearly a Decade for Patients With Myelofibrosis". ir.celgene.com. Retrieved 16 August 2019.
- "AbbVie Receives FDA Approval of RINVOQ™ (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid Arthritis | AbbVie News Center". news.abbvie.com. Retrieved 16 August 2019.
- "Clinical Trials with GLPG0634". ClinicalTrials.gov. Retrieved 16 July 2016.
- 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.
- "Clinical trials with LY2784544 (Gandotinib)". ClinicalTrials.gov. Retrieved 16 July 2016.
- 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.
- "Momelotinib in Transfusion-Dependent Adults with Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF)". ClinicalTrials.gov. Retrieved 16 July 2016.
- "Momelotinib Combined with Capecitabine and Oxaliplatin in Adults with Relapsed/Refractory Metastatic Pancreatic Ductal Adenocarcinoma". ClinicalTrials.gov. Retrieved 16 July 2016.
- Hart S, Goh KC, Novotny-Diermayr V, Hu CY, Hentze H, Tan YC, Madan B, Amalini C, Loh YK, Ong LC, William AD, Lee A, Poulsen A, Jayaraman R, Ong KH, Ethirajulu K, Dymock BW, Wood JW (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.
- "Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis with Thrombocytopenia". ClinicalTrials.gov. Retrieved 16 July 2016.
- "Pacritinib in Combination with Low Dose Decitabine in Intermediate-High Risk Myelofibrosis or Myeloproliferative Neoplasm (MPN)/Myelodysplastic Syndrome (MDS)". ClinicalTrials.gov. Retrieved 16 July 2016.
- "Clinical Trials with PF04965842". ClinicalTrials.gov. Retrieved 21 May 2017.
- 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.
- 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.
- Stallard, J (23 July 2015). "Discovery Could Boost New Therapies for Myeloproliferative Neoplasms". Memorial Sloan Kettering Cancer Center. Retrieved 16 July 2016.
- Gershon, E (19 June 2014). "In Hairless Man, Arthritis Drug Spurs Hair Growth — Lots of It". Yale News. Retrieved 16 July 2016.
- 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.
- Shreberk-Hassidim R, Ramot Y, Zlotogorski A (April 2017). "Janus kinase inhibitors in dermatology: A systematic review". Journal of the American Academy of Dermatology. 76 (4): 745–753.e19. doi:10.1016/j.jaad.2016.12.004. PMID 28169015.