AJanus kinase inhibitor, also known asJAK inhibitor orjakinib,[1] is a type of immune modulating medication, which inhibits the activity of one or more of theJanus kinase family of enzymes (JAK1,JAK2,JAK3,TYK2), thereby interfering with theJAK-STAT signaling pathway inlymphocytes.
JAK enzymes are part of the JAK/STAT pathway. This signaling pathway transmits chemical signals from the outside of cells, specifically lymphocytes, and into thecell nucleus. Signals relayed by JAK3 aid in the maturation and regulation of growth ofT cells andnatural 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 causesynovial inflammation, joint destruction, andautoantibody production. JAK3 inhibitors necessarily cause a loss or total absence of T cells and natural killer cells while leaving a normal amount ofB cells. The loss of these essential lymphocytes cause a person to become highly susceptible toinfection; moreover, usually JAK3 inhibitors are used by people with an autoimmune disease, who are already at a greater risk forinfection.[6]
ThePharmacovigilance Risk Assessment Committee of theEuropean Medicines Agency (EMA) recommends that the Janus kinase inhibitorsabrocitinib,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 asheart attack orstroke), those whosmoke 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 ofVaricella zoster virus (VZV) infection.[11] Several guidelines suggest investigating patients' vaccination status before starting any treatment and performing vaccinations againstVaccine-preventable disease when required.[12][13]Nevertheless, a low vaccination rate ofHerpes zoster vaccine was found among cohorts of patients withIBD, 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 controllingcell growth and theimmune response. Many cytokines function by binding to and activatingtype I cytokine receptors andtype II cytokine receptors. These receptors in turn rely on theJanus kinase (JAK) family of enzymes forsignal 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 kinasesphosphorylate activated cytokine receptors. These phosphorylated receptors in turn recruitSTATtranscription factors which modulate gene transcription.[16]
The first JAK inhibitor to reach clinical trials wastofacitinib. Tofacitinib is a specific inhibitor ofJAK3 (IC50 = 2 nM) thereby blocking the activity ofIL-2,IL-4,IL-15 andIL-21. HenceTh2cell differentiation is blocked and therefore tofacitinib is effective in treating allergic diseases. Tofacitinib to a lesser extent also inhibitsJAK1 (IC50 = 100 nM) andJAK2 (IC50 = 20 nM), which in turn blocksIFN-γ andIL-6 signalling and consequently Th1 cell differentiation.[1]
One mechanism (relevant to psoriasis) is that the blocking of Jak-dependentIL-23 reducesIL-17 and the damage it causes.[4]
JAK3 inhibitors target the catalyticATP-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 ispyrrolopyrimidine, 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 thestructure activity relationship of may be found inthe article on JAK3 inhibitors.
Z583, a JAK3 selective inhibitor, was developed in 2022. JAK3 only regulates certaingamma c cytokines, and Z583 completely inhibited gamma c signaling and blocked the development of inflammatory response.[66]
^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, et al. (June 2021). "Current jakinibs for the treatment of rheumatoid arthritis: a systematic review".Inflammopharmacology.29 (3):595–615.doi:10.1007/s10787-021-00822-x.PMID34046798.
^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.
^Leit S, Greenwood J, Carriero S, Mondal S, Abel R, Ashwell M, et al. (August 2023). "Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279".Journal of Medicinal Chemistry.66 (15):10473–10496.doi:10.1021/acs.jmedchem.3c00600.PMID37427891.
