Janus kinase inhibitor
Introduction A '''Janus kinase inhibitor''', also known as '''JAK inhibitor''' or '''jakinib''', 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 such as rheumatoid arthritis and various skin conditions. 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.
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.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. 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.
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.More specifically, Janus kinases phosphorylate activated cytokine receptors. These phosphorylated receptors in turn recruit STAT transcription factors which modulate gene transcription.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.
Molecule design In September 2021, the U.S. Food and Drug Administration (FDA) approved the first JAK inhibitor, ruxolitinib, to treat a skin condition.Some JAK1 inhibitors are based on a benzimidazole core.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. Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo2,3-bpyridine, as it mimics the pyrrolopyrimidine scaffold. 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   * Primary and secondary myelofibrosis (intermediate or high-risk)* Polycythemia vera resistant or intolerant to hydroxyurea* Steroid-refractory acute GVHD* Chronic GVHD (second or third-line therapy)  Tofacitinib  Xeljanz, Xeljanz XR, Jaquinus  JAK1, JAK2, JAK3   * Moderate-to-severe active rheumatoid arthritis* Active psoriatic arthritis* Active ankylosing spondylitis* Moderate-to-severe active ulcerative colitis* Active polyarticular course juvenile idiopathic arthritisIndicated in intolerance or inefficacy of TNF inhibitors or DMARDs, or other conventional therapy or biologic agents  Oclacitinib  Apoquel  JAK1  May 2013 (US) * Pruritus associated with allergic dermatitis in dogs* Atopic dermatitis in dogs  Baricitinib  Olumiant  JAK1, JAK2   * Moderate-to-severe active rheumatoid arthritis (in inadequate response to TNF inhibitors or DMARDs)* Severe COVID-19* Severe alopecia areata  Peficitinib  Smyraf  JAK1, JAK3   * Rheumatoid arthritis with inadequate response to standard therapy or DMARDs  Upadacitinib  Rinvoq  JAK1   * Moderate-to-severe active rheumatoid arthritis* Active psoriatic arthritis* Active ankylosing spondylitis* Moderate-to-severe atopic dermatitis* Moderate-to-severe active ulcerative colitis* Active non-radiographic axial spondyloarthritisIndicated in intolerance or inefficacy of TNF inhibitors or DMARDs, or other conventional therapy or biologic agents  Fedratinib  Inrebic  JAK2   * Primary and secondary myelofibrosis (intermediate-2 or high-risk)  Delgocitinib (topical)  Corectim  Non-selective  January 2020 (Japan) * Atopic dermatitis  Filgotinib  Jyseleca  JAK1  September 2020 (EU, Japan) * Moderate-to-severe active rheumatoid arthritis* Moderate-to-severe active ulcerative colitisIndicated in intolerance or inefficacy of DMARDs or conventional therapy  Abrocitinib  Cibinqo  JAK1   * Refractory moderate-to-severe atopic dermatitis with inadequate response to other systemic therapy  Ruxolitinib (topical)  Opzelura  JAK1, JAK2  September 2021 (US) * Moderate-to-severe atopic dermatitis (not as a first-line therapy)* Nonsegmental vitiligo  Pacritinib  Vonjo  JAK2  February 2022 (US) * Primary and secondary myelofibrosis (intermediate or high-risk) with thrombocytopenia  Deucravacitinib  Sotyktu  TYK2  September 2022 (US) * Moderate-to-severe plaque psoriasis  Ritlecitinib  Litfulo  JAK3  June 2023 (US) * Severe alopecia areata  Momelotinib  Ojjaara  JAK1, JAK2  September 2023 (US) * Intermediate- or high-risk myelofibrosis in adults with anemia === In clinical trials ===* 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) for relapsed lymphoma and advanced myeloid malignancies, also myelofibrosis, myeloproliferative neoplasms and myelodysplastic syndrome. * Deucravacitinib is currently in clinical trials for psoriatic arthritis, inflammatory bowel disease and systemic lupus erythematosus.=== Experimental drugs/indications ===* 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.
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