Janus kinase inhibitor
A Janus kinase inhibitor, also known as JAK inhibitor or jakinib,
It is used in the treatment of cancer and
Contraindications
JAK3 is an enzyme in the body that is apart of the JAK/STAT pathway. This signaling pathway transmits chemical signals from the outside of cells, specifically lymphocytes, and into the nucleus of these cells. 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. By using a JAK3 inhibitor, there inevitably becomes a loss of JAK3 protein which in turn causes a loss or total absence of T cells, natural killer cells, and a normal amount of B cells. The loss of these essential lymphocytes cause a person to become highly susceptible to infection, however usually the inhibitor is only used by people with an autoimmune disease and are already at a greater risk for infection.[8]
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.[9][10]
The Pharmacovigilance Risk Assessment Committee of the
The special warnings by FDA and EMA are important for shared-decision making with the patient.[13]
Mechanism of action
Janus kinase inhibitors can be classed in several overlapping classes: they are
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
The first JAK inhibitor to reach clinical trials was
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.[15]
Some JAK1 inhibitors are based on a benzimidazole core.[16]
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.[17][18] Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo[2,3-b]pyridine, as it mimics the pyrrolopyrimidine scaffold.[19] 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 |
|
|
[20][21] |
Tofacitinib | Xeljanz, Xeljanz XR, Jaquinus | JAK1, JAK2, JAK3 |
|
Indicated in intolerance or inefficacy of TNF inhibitors or DMARDs, or other conventional therapy or biologic agents |
[22][23] |
Oclacitinib | Apoquel | JAK1 | May 2013 (US) |
|
[24][25][26] |
Baricitinib | Olumiant | JAK1, JAK2 |
|
|
[27][28] |
Peficitinib | Smyraf | JAK1, JAK3 |
|
|
[29][30][31] |
Upadacitinib | Rinvoq | JAK1 |
|
Indicated in intolerance or inefficacy of TNF inhibitors or DMARDs, or other conventional therapy or biologic agents |
[32] |
Fedratinib | Inrebic | JAK2 |
|
|
[33][34] |
Delgocitinib (topical) | Corectim | Non-selective | January 2020 (Japan) | [35] | |
Filgotinib | Jyseleca | JAK1 | September 2020 (EU, Japan) |
Indicated in intolerance or inefficacy of DMARDs or conventional therapy |
[36] |
Abrocitinib | Cibinqo | JAK1 |
|
|
[37][38][39] |
Ruxolitinib (topical) | Opzelura | JAK1, JAK2 | September 2021 (US) |
|
[40] |
Pacritinib | Vonjo | JAK2 | February 2022 (US) |
|
[41] |
Deucravacitinib | Sotyktu | TYK2 | September 2022 (US) |
|
[42] |
Ritlecitinib | Litfulo | JAK3 | June 2023 (US) |
|
[43] |
Momelotinib | Ojjaara | JAK1, JAK2 | September 2023 (US) |
|
[44] |
In clinical trials
- Cerdulatinib (PRT062070) dual SYK/JAK inhibitor for hematological malignancies.[45]
- Gandotinib (LY-2784544) against JAK2 for myeloproliferative neoplasms.[46]
- Lestaurtinib (CEP-701) against JAK2 for acute myeloid leukemia (AML).[47]
- Momelotinib (GS-0387, CYT-387) against JAK1 and JAK2 for myeloproliferative disorders[48] and relapsed/refractory metastatic pancreatic cancer.[49]
- Pacritinib (SB1518) for relapsed myeloid malignancies,[50] also myelofibrosis,[51] myeloproliferative neoplasms and myelodysplastic syndrome.[52]
- Deucravacitinib is currently in clinical trials for systemic lupus erythematosus.[53]
Experimental drugs/indications
- Cucurbitacin I (JSI-124).[54]
- CHZ868 — a type II JAK2 inhibitor for use in myeloproliferative disorders and chronic myelomonocytic leukemia (CMML).[55][56]
- Tofacitinib for alopecia universalis.[57]
- Topical tofacitinib and ruxolitinib for alopecia.[58]
References
- ^ PMID 22819198.
- PMID 18613833.
- S2CID 21143324.
- ^ a b "JAK Inhibitors Showing Promise for Many Skin Problems - Conditions ranging from alopecia to vitiligo". 6 July 2017. Archived from the original on 13 July 2017. Retrieved 9 July 2017.
- ^ Tanaka, Yoshiya; Luo, Yiming; O'Shea, John J.; Nakayamada, Shingo (5 January 2022). "Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach". Nature Reviews. Retrieved 9 March 2024.
- PMID 28844493.
- ^ Chengjuan, Chen; et al. (19 August 2022). "A highly selective JAK3 inhibitor is developed for treating rheumatoid arthritis by suppressing γc cytokine-related JAK-STAT signal". PubMed. Retrieved 6 May 2024.
- ^ "JAK3-deficient severe combined immunodeficiency". Medline Plus. 1 August 2017. Retrieved 6 May 2024.
- ^ "Janus Kinase (JAK) inhibitors: Drug Safety Communication - FDA Requires Warnings about Increased Risk of Serious Heart-related Events, Cancer, Blood Clots, and Death". U.S. Food and Drug Administration (FDA). 2 September 2021. Archived from the original on 28 October 2022. Retrieved 28 October 2022.
- ^ "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". U.S. Food and Drug Administration (FDA). 6 December 2021. Archived from the original on 28 October 2022. Retrieved 28 October 2022.
- ^ a b "EMA recommends measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders". European Medicines Agency (EMA) (Press release). 28 October 2022. Retrieved 28 October 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
- ^ "Janus Kinase inhibitors (JAKi)". European Medicines Agency (EMA). 28 October 2022. Archived from the original on 28 October 2022. Retrieved 28 October 2022.
- PMID 35197363.
- PMID 23743669.
- ^ "JAK inhibitors: What your dermatologist wants you to know". www.aad.org. Retrieved 30 July 2023.
- PMID 26351728.
- PMID 24417533.
- PMID 26258521.
- ^ "Synthesis and Evaluation of 1 H -Pyrrolo[2,3- b ]pyridine Derivatives as Novel Immunomodulators Targeting Janus Kinase 3 (PDF Download Available)". ResearchGate. Retrieved 26 September 2017.
- S2CID 29293800.
- ^ "Jakafi (ruxolitinib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Incyte Corporation. Archived (PDF) from the original on 2 April 2016. Retrieved 16 July 2016.
- S2CID 12226975.
- ^ "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. Archived from the original on 14 April 2019. Retrieved 16 July 2016.
- PMID 24495176.
- ^ "FDA Approves Apoquel (oclacitinib tablet) to Control Itch and Inflammation in Allergic Dogs" (Press release). Zoetis. 16 May 2013. Archived from the original on 23 February 2017. Retrieved 23 February 2017.
- ^ "Apoquel- oclacitinib maleate tablet, coated". DailyMed. 28 July 2021. Retrieved 25 June 2023.
- ^ "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. Archived from the original on 21 August 2018. Retrieved 21 August 2018.
- ^ "FDA Approves First Systemic Treatment for Alopecia Areata". U.S. Food and Drug Administration (FDA) (Press release). 13 June 2022. Retrieved 10 August 2022.
- PMID 27748083.
- PMID 28118538.
- S2CID 155093525.
- ^ "AbbVie Receives FDA Approval of Rinvoq (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid Arthritis". AbbVie (Press release). Retrieved 16 August 2019.
- ^ "FDA approves treatment for patients with rare bone marrow disorder". U.S. Food and Drug Administration (FDA) (Press release). 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" (Press release). Celgene. 16 August 2019. Retrieved 25 June 2023 – via Business Wire.
- S2CID 212681247.
- ^ "Clinical Trials with GLPG0634". ClinicalTrials.gov. Archived from the original on 18 October 2016. Retrieved 16 July 2016.
- ^ "Clinical Trials with PF04965842". ClinicalTrials.gov. Archived from the original on 31 August 2021. Retrieved 21 May 2017.
- ^ "Abrocitinib (PF-04965842)". MedChemExpress. Archived from the original on 19 March 2020. Retrieved 21 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. 20 November 2019. Archived from the original on 22 February 2020. Retrieved 21 November 2019.
- ^ "Opzelura (ruxolitinib) Cream, for Topical Use. Full Prescribing Information" (PDF). Incyte Corporation. Archived (PDF) from the original on 28 August 2022. Retrieved 10 September 2022.
- ^ "Vonjo (pacritinib) Capsules, for Oral Use. Full Prescribing Information" (PDF). CTI BioPharma Corp. Archived (PDF) from the original on 10 September 2022. Retrieved 10 September 2022.
- ^ "Sotyktu (deucravacitinib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Bristol-Myers Squibb Company. Archived (PDF) from the original on 10 September 2022. Retrieved 10 September 2022.
- ^ "Litfulo (ritlecitinib) Capsules, for Oral Use. Full Prescribing Information". Pfizer, Inc.
- ^ "Ojjaara (momelotinib) Tablets, for Oral Use. Full Prescribing Information". DailyMed. 15 September 2023. Retrieved 20 September 2023.
- PMID 28754125.
- ^ "Clinical trials with LY2784544 (Gandotinib)". ClinicalTrials.gov. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
- S2CID 13558158.
- ^ "Momelotinib in Transfusion-Dependent Adults with Primary Myelofibrosis (PMF) or Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis (Post-PV/ET MF)". ClinicalTrials.gov. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
- ^ "Momelotinib Combined with Capecitabine and Oxaliplatin in Adults with Relapsed/Refractory Metastatic Pancreatic Ductal Adenocarcinoma". ClinicalTrials.gov. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
- PMID 21691275.
- ^ "Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis with Thrombocytopenia". ClinicalTrials.gov. Archived from the original on 6 August 2016. 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. Archived from the original on 6 August 2016. Retrieved 16 July 2016.
- ^ "BMS-986165 Phase 2, 3". ClinicalTrials.gov. Archived from the original on 12 April 2021. Retrieved 29 July 2020.
- from the original on 17 September 2016. Retrieved 16 July 2016.
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- ^ Stallard J (23 July 2015). "Discovery Could Boost New Therapies for Myeloproliferative Neoplasms". Memorial Sloan Kettering Cancer Center. Archived from the original on 16 June 2016. Retrieved 16 July 2016.
- ^ Gershon E (19 June 2014). "In Hairless Man, Arthritis Drug Spurs Hair Growth — Lots of It". Yale News. Archived from the original on 19 July 2016. Retrieved 16 July 2016.
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