Janus kinase inhibitor

Contraindications

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.

The US Food and Drug Administration (FDA) requires a boxed warning for the JAK inhibitors tofacitinib, baricitinib, and upadacitinib to warn 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.

Patients of all ages treated with Janus kinase inhibitors are at higher risk of Varicella zoster virus (VZV) infection. Several guidelines suggest investigating patients' vaccination status before starting any treatment and performing vaccinations against Vaccine-preventable disease when required. Nevertheless, a low vaccination rate of Herpes zoster vaccine was found among cohorts of patients with IBD, despite a generally positive attitude towards vaccinations.

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 signaling. 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 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-pyrrolo[2,3-b]pyridine, 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

In clinical trials

• Brepocitinib (PF-06700841), dual JAK1/TYK2 inhibitor for plaque psoriasis.
• Cerdulatinib (PRT062070) dual SYK/JAK inhibitor for hematological malignancies.
• Decernotinib (VX-509), effective in clinical trials against rheumatoid arthritis but failed to show advantages over related compounds.
• Izencitinib (TD-1473), gut selective pan-JAK inhibitor for inflammatory bowel disease.
• Gandotinib (LY-2784544) against JAK2 for myeloproliferative neoplasms.
• Gusacitinib (ASN002), dual JAK/SYK inhibitor in clinical trials for eczema.
• Lestaurtinib (CEP-701) against JAK2 for acute myeloid leukemia (AML).
• Povorcitinib (INCB054707), JAK1 inhibitor in clinical trials for hidradenitis suppurativa and chronic prurigo.
• Ropsacitinib (PF-06826647), selective TYK2 inhibitor for plaque psoriasis.
• Zasocitinib (TAK-279), TYK2 inhibitor for the treatment of psoriatic arthritis.

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.
• VVD-118313, selective JAK1 allosteric inhibitor.
• 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.

References

References

1. (August 2012). "Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease". Current Opinion in Pharmacology.
2. (June 2008). "Therapeutic targeting of Janus kinases". Immunological Reviews.
3. (August 2014). "Selective JAK inhibitors in development for rheumatoid arthritis". Expert Opinion on Investigational Drugs.
4. (6 July 2017). "JAK Inhibitors Showing Promise for Many Skin Problems - Conditions ranging from alopecia to vitiligo".
5. (January 5, 2022). "Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach". Nature Reviews Rheumatology.
6. (August 1, 2017). "JAK3-deficient severe combined immunodeficiency".
7. (2 September 2021). "Janus Kinase (JAK) inhibitors: Drug Safety Communication - FDA Requires Warnings about Increased Risk of Serious Heart-related Events, Cancer, Blood Clots, and Death".
8. (6 December 2021). "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".
9. (28 October 2022). "EMA recommends measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders".
10. (28 October 2022). "Janus Kinase inhibitors (JAKi)".
11. (2018). "Herpes Zoster Infection in Patients with Ulcerative Colitis Receiving Tofacitinib". Inflamm. Bowel Dis..
12. (2021). "ECCO Guidelines on the Prevention, Diagnosis, and Management of Infections in Inflammatory Bowel Disease". J. Crohn's Colitis.
13. (2019). "British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults". Gut.
14. (2023). "Attitudes towards Vaccinations in a National Italian Cohort of Patients with Inflammatory Bowel Disease". Vaccines.
15. (2022). "Waiting for JAK inhibitor safety data". RMD Open.
16. (October 2013). "The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders". BioDrugs.
17. "JAK inhibitors: What your dermatologist wants you to know".
18. (2015). "Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors". Journal of Medicinal Chemistry.
19. (June 2014). "Discovery and development of Janus kinase (JAK) inhibitors for inflammatory diseases". Journal of Medicinal Chemistry.
20. (August 2015). "Development of Selective Covalent Janus Kinase 3 Inhibitors". Journal of Medicinal Chemistry.
21. "Synthesis and Evaluation of 1 H -Pyrrolo[2,3- b ]pyridine Derivatives as Novel Immunomodulators Targeting Janus Kinase 3 (PDF Download Available)".
22. (November 2012). "Ruxolitinib, an oral JAK1 and JAK2 inhibitor, in myelofibrosis". Expert Opinion on Pharmacotherapy.
23. "Jakafi (ruxolitinib) Tablets, for Oral Use. Full Prescribing Information". Incyte Corporation.
24. (May 2012). "Tofacitinib for the treatment of rheumatoid arthritis". Expert Review of Clinical Immunology.
25. "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.
26. (August 2014). "Oclacitinib (Apoquel) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy". Journal of Veterinary Pharmacology and Therapeutics.
27. (16 May 2013). "FDA Approves Apoquel (oclacitinib tablet) to Control Itch and Inflammation in Allergic Dogs". Zoetis.
28. (28 July 2021). "Apoquel- oclacitinib maleate tablet, coated".
29. (1 June 2018). "FDA Approves Olumiant (baricitinib) 2-mg Tablets for the Treatment of Adults with Moderately-to-Severely Active Rheumatoid Arthritis".
30. (13 June 2022). "FDA Approves First Systemic Treatment for Alopecia Areata".
31. Hoy, Sheridan M.. (May 2022). "Baricitinib: A Review in Moderate to Severe Atopic Dermatitis". American Journal of Clinical Dermatology.
32. (2018-01-25). "Olumiant {{!}} European Medicines Agency (EMA)".
33. (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.
34. (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.
35. (June 2019). "Peficitinib: First Global Approval". Drugs.
36. "AbbVie Receives FDA Approval of Rinvoq (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid Arthritis".
37. (16 August 2019). "FDA approves treatment for patients with rare bone marrow disorder".
38. (16 August 2019). "U.S. FDA Approves Inrebic (Fedratinib) as First New Treatment in Nearly a Decade for Patients With Myelofibrosis". Celgene.
39. (April 2020). "Delgocitinib: First Approval". Drugs.
40. "Clinical Trials with GLPG0634". ClinicalTrials.gov.
41. "Clinical Trials with PF04965842". ClinicalTrials.gov.
42. (20 November 2019). "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.
43. "Opzelura (ruxolitinib) Cream, for Topical Use. Full Prescribing Information". Incyte Corporation.
44. "Vonjo (pacritinib) Capsules, for Oral Use. Full Prescribing Information". CTI BioPharma Corp..
45. "Sotyktu (deucravacitinib) Tablets, for Oral Use. Full Prescribing Information". Bristol-Myers Squibb Company.
46. "Litfulo (ritlecitinib) Capsules, for Oral Use. Full Prescribing Information". Pfizer, Inc..
47. (15 September 2023). "Ojjaara (momelotinib) Tablets, for Oral Use. Full Prescribing Information".
48. (2024). "Golidocitinib: First Approval". Drugs.
49. (25 July 2024). "Leqselvi (deuruxolitinib) Tablets, for Oral Use. Full Prescribing Information".
50. "Zenrelia".
51. (2023). "Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway". Journal of Cutaneous Medicine and Surgery.
52. (July 2017). "Syk inhibitors in clinical development for hematological malignancies". Journal of Hematology & Oncology.
53. (Jun 2021). "Current jakinibs for the treatment of rheumatoid arthritis: a systematic review". Inflammopharmacology.
54. (Mar 2022). "Gut-Selective Design of Orally Administered Izencitinib (TD-1473) Limits Systemic Exposure and Effects of Janus Kinase Inhibition in Nonclinical Species". Toxicol Sci.
55. "Clinical trials with LY2784544 (Gandotinib)". ClinicalTrials.gov.
56. (August 2023). "Oral spleen tyrosine kinase/Janus Kinase inhibitor gusacitinib for the treatment of chronic hand eczema: Results of a randomized phase 2 study". Journal of the American Academy of Dermatology.
57. (March 2010). "Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside". Expert Opinion on Investigational Drugs.
58. (May 2022). "Janus kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa: results from two phase II studies". Br J Dermatol.
59. (August 2022). "Oral tyrosine kinase 2 inhibitor PF-06826647 demonstrates efficacy and an acceptable safety profile in participants with moderate-to-severe plaque psoriasis in a phase 2b, randomized, double-blind, placebo-controlled study". Journal of the American Academy of Dermatology.
60. (August 2023). "Discovery of a Potent and Selective Tyrosine Kinase 2 Inhibitor: TAK-279". Journal of Medicinal Chemistry.
61. (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.
62. (July 2015). "CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms". Cancer Cell.
63. (23 July 2015). "Discovery Could Boost New Therapies for Myeloproliferative Neoplasms". Memorial Sloan Kettering Cancer Center.
64. (19 June 2014). "In Hairless Man, Arthritis Drug Spurs Hair Growth — Lots of It". Yale News.
65. (October 2015). "Pharmacologic inhibition of JAK-STAT signaling promotes hair growth". Science Advances.
66. (2022). "Selective inhibitors of JAK1 targeting an isoform-restricted allosteric cysteine". Nat Chem Biol.
67. (August 2022). "A highly selective JAK3 inhibitor is developed for treating rheumatoid arthritis by suppressing γc cytokine-related JAK-STAT signal". Science Advances.