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 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 infection.[6]
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]
Patients of all ages treated with Janus kinase inhibitors are at higher risk of Varicella zoster virus (VZV) infection.[11] Several guidelines suggest investigating patients’ vaccination status before starting any treatment and performing vaccinations against Vaccine-preventable disease when required. [12][13]
Nevertheless, a low vaccination rate of Herpes zoster vaccine was found among cohorts of patients with IBD, despite a generally positive attitude towards vaccinations. [14]
The special warnings by FDA and EMA are important for shared-decision making with the patient.[15]
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 STATtranscription factors which modulate gene transcription.[16]
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 Th2cell 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.[17]
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.[19][20] Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo[2,3-b]pyridine, as it mimics the pyrrolopyrimidine scaffold.[21] More information on the structure activity relationship of may be found in the article on JAK3 inhibitors.
Z583, a JAK3 selective inhibitor, was developed in 2022. JAK3 only regulates certain gamma c cytokines, and Z583 completely inhibited gamma c signaling and blocked the development of inflammatory response.[64]
^Winthrop, K.L.; Melmed, G.Y.; Vermeire, S.; Long, M.D.; Chan, G.; Pedersen, R.D.; Lawendy, N.; Thorpe, A.J.; Nduaka, C.I.; Su, C. Herpes Zoster Infection in Patients with Ulcerative Colitis Receiving Tofacitinib. Inflamm. Bowel Dis. 2018, 24, 2258–2265
^Kucharzik, T.; Ellul, P.; Greuter, T.; Rahier, J.F.; Verstockt, B.; Abreu, C.; Albuquerque, A.; Allocca, M.; Esteve, M.; Farraye, F.A.; et al. ECCO Guidelines on the Prevention, Diagnosis, and Management of Infections in Inflammatory Bowel Disease. J. Crohn’s Colitis 2021, 15, 879–913
^Lamb, C.A.; Kennedy, N.A.; Raine, T.; Hendy, P.A.; Smith, P.J.; Limdi, J.K.; Hayee, B.H.; Lomer, M.C.; Parkes, G.C.; Selinger, C.; et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019, 68 (Suppl. S3), s1–s106
^Costantino, A.; Michelon, M.; Noviello, D.; Macaluso, F.S.; Leone, S.; Bonaccorso, N.; Costantino, C.; Vecchi, M.; Caprioli, F., on behalf of AMICI Scientific Board. Attitudes towards Vaccinations in a National Italian Cohort of Patients with Inflammatory Bowel Disease. Vaccines 2023, 11, 1591. https://doi.org/10.3390/vaccines11101591
^Kyoung Kim M, Shin H, Kwang-su P, Kim H, Park J, Kim K, et al. (2015). "Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors". Journal of Medicinal Chemistry. 58 (18): 7596–7602. doi:10.1021/acs.jmedchem.5b01263. PMID26351728.
^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. PMID24417533.
^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. PMID22607178. S2CID12226975.
^Loo WJ, Turchin I, Prajapati VH, Gooderham MJ, Grewal P, Hong CH, et al. (2023). "Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway". Journal of Cutaneous Medicine and Surgery. 27 (1_suppl): 3S–24S. doi:10.1177/12034754221141680. PMID36519621.
^Rocha CM, Alves AM, Bettanin BF, Majolo F, Gehringer M, Laufer S, Goettert MI. Current jakinibs for the treatment of rheumatoid arthritis: a systematic review. Inflammopharmacology. 2021 Jun;29(3):595-615. doi:10.1007/s10787-021-00822-xPMID34046798
^Hardwick RN, Brassil P, Badagnani I, Perkins K, Obedencio GP, Kim AS, Conner MW, Bourdet DL, Harstad EB. Gut-Selective Design of Orally Administered Izencitinib (TD-1473) Limits Systemic Exposure and Effects of Janus Kinase Inhibition in Nonclinical Species. Toxicol Sci. 2022 Mar 28;186(2):323-337. doi:10.1093/toxsci/kfac002PMID35134999
^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. PMID20141349. S2CID13558158.
^Alavi A, Hamzavi I, Brown K, Santos LL, Zhu Z, Liu H, Howell MD, Kirby JS. Janus kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa: results from two phase II studies. Br J Dermatol. 2022 May;186(5):803-813. doi:10.1111/bjd.20969PMID34978076
