مثبط الكيناز جانوس
مثبطات الكيناز جانوس (إنگليزية: Janus kinase inhibitors)، أو مثبطات JAK (إنگليزية: JAK inhibitors، أو jakinibs)،[1] هي نوع من الأدوية التي تعمل عن طريق تثبيط نشاط واحد أو أكثر من عائلة إنزيمات كيناز جانوس (JAK1، JAK2، JAK3، TYK2)، وبالتالي تتداخل مع مسار تأشير JAK-STAT.
لهذه المثبطات تطبيقات علاجية في علاج السرطان والأمراض الالتهابية[1][2] مثل التهاب المفاصل الرثياني.[3] هناك اهتمام في استخدامها لعلاج أمراض جلدية مختلفة.[4] مثبطات JAK3 هي علاج محتمل لأمراض مناعية مختلفة حيث أن وظيفتها الأساسية تقتصر الخلايا اللمفاوية. جاري العمل على تطوير مثبطات JAK3 منذ عام 2017.[5]
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آلية العمل
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 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.[1]
More specifically, Janus kinases phosphorylate activated cytokine receptors. These phosphorylated receptors in turn recruit STAT transcription factors which modulate gene transcription.[6]
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.[1]
One mechanism (relevant to psoriasis) is that the blocking of Jak-dependent IL-23 reduces IL-17 and the damage it causes.[4]
التصميم الجزيئي
Some JAK1 inhibitors are based on a benzimidazole core.[7]
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.[8][9] Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo[2,3-b]pyridine, as it mimics the pyrrolopyrimidine scaffold.[10] More information on the structure activity relationship of may be found in the article on JAK3 inhibitors.
أمثلة
مركبات معتمدة
- روكسوليتينيب (الأسماء التجارية جكافي، جكاڤي) ضد JAK1/JAK2، لعلاج التليف النقوي وكثرة الحمر الحقيقية.[11] اعتمدته
Approved by the U.S. FDA in November 2011 for myelofibrosis (intermediate- or high-risk) and polycythemia vera, in patients with an inadequate response or intolerance to hydroxyurea.[12] اعتمد روكسوليتينيب كريم (الاسم التجاري أوپزلورا) لعلاج التهاب الجلد التأتبي للأشخاص الذين يبلغون 12 عام وأكثر. كما اعتمدته منظمة الصحة العالمية لعلاج البهاق.
- Tofacitinib (trade names Xeljanz/Jakvinus, formerly known as tasocitinib and CP-690550) against JAK3 for psoriatic arthritis and rheumatoid arthritis.[13] U.S. FDA approved it in November 2012 for rheumatoid arthritis (moderately-to-severely active) in patients who had an inadequate response or intolerance to methotrexate.[14]
- Oclacitinib (trade name Apoquel) — against JAK1[15] for the control of pruritus associated with allergic dermatitis and the control of atopic dermatitis in dogs at least 12 months of age.[16][17]
- Baricitinib (trade name Olumiant) against JAK1/JAK2 for rheumatoid arthritis.[18]
- Peficitinib (ASP015K, JNJ-54781532; trade name Smyraf) mainly inhibits JAK3 and used for treatment of rheumatoid arthritis.[19][20] Approved for use in Japan in 2019.[21]
- Fedratinib (SAR302503; trade name Inrebic) is a JAK2 inhibitor for treatment of primary myelofibrosis (including in patients those previously treated with ruxolitinib), or secondary myelofibrosis (post-polycythemia vera or post-essential thrombocythemia. Approved by U.S. FDA on 16 August 2019.[22][23]
- Upadacitinib (trade name Rinvoq; ABT-494) against JAK1 for rheumatoid arthritis and atopic dermatitis. Approved by U.S FDA on 16 August 2019.[24]
- Filgotinib (G-146034, GLPG-0634) against JAK1 for rheumatoid arthritis and Crohn's disease.[25] Approved in European Union and Japan in September 2020.
- Delgocitinib, approved in Japan for the treatment of atopic dermatitis.[26]
- Abrocitinib (Cibinqo, PF-04965842) against JAK1 approved for atopic dermatitis and under study for moderate to severe psoriasis. [27][28][29]
في التجارب السريرية
- Cerdulatinib (PRT062070) dual SYK/JAK inhibitor for hematological malignancies.[30]
- Gandotinib (LY-2784544) against JAK2 for myeloproliferative neoplasms.[31]
- Lestaurtinib (CEP-701) against JAK2 for acute myeloid leukemia (AML).[32]
- Momelotinib (GS-0387, CYT-387) against JAK1 and JAK2 for myeloproliferative disorders[33] and relapsed/refractory metastatic pancreatic cancer.[34]
- Pacritinib (SB1518) against JAK2 for relapsed lymphoma and advanced myeloid malignancies,[35] also myelofibrosis,[36] myeloproliferative neoplasms and myelodysplastic syndrome.[37]
- Deucravacitinib (BMS-986165) against TYK2 for psoriasis, psoriatic arthritis, inflammatory bowel disease and systemic lupus erythematosus. Currently in Phase III trials for psoriasis and Phase II for other conditions.[38]
الأدوية التجريبية/دواعي الاستعمال
- Cucurbitacin I (JSI-124).[39]
- CHZ868 — a type II JAK2 inhibitor for use in myeloproliferative disorders and chronic myelomonocytic leukemia (CMML).[40][41]
- Tofacitinib for alopecia universalis.[42]
- Topical tofacitinib and ruxolitinib for alopecia.[43]
المصادر
- ^ أ ب ت ث Kontzias A, Kotlyar A, Laurence A, Changelian P, O'Shea JJ (August 2012). "Jakinibs: a new class of kinase inhibitors in cancer and autoimmune disease". Current Opinion in Pharmacology. 12 (4): 464–70. doi:10.1016/j.coph.2012.06.008. PMC 3419278. PMID 22819198.
- ^ Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ (June 2008). "Therapeutic targeting of Janus kinases". Immunological Reviews. 223: 132–42. doi:10.1111/j.1600-065X.2008.00644.x. PMC 2634846. PMID 18613833.
- ^ Norman P (August 2014). "Selective JAK inhibitors in development for rheumatoid arthritis". Expert Opinion on Investigational Drugs. 23 (8): 1067–77. doi:10.1517/13543784.2014.918604. PMID 24818516. S2CID 21143324.
- ^ أ ب "JAK Inhibitors Showing Promise for Many Skin Problems - Conditions ranging from alopecia to vitiligo". 6 July 2017.
- ^ Forster M, Gehringer M, Laufer SA (September 2017). "Recent advances in JAK3 inhibition: Isoform selectivity by covalent cysteine targeting". Bioorganic & Medicinal Chemistry Letters. 27 (18): 4229–4237. doi:10.1016/j.bmcl.2017.07.079. PMID 28844493.
- ^ Furumoto Y, Gadina M (October 2013). "The arrival of JAK inhibitors: advancing the treatment of immune and hematologic disorders". BioDrugs. 27 (5): 431–8. doi:10.1007/s40259-013-0040-7. PMC 3778139. PMID 23743669.
- ^ Kyoung Kim M, Shin H, Kwang-su P, Kim H, Park J, Kim K, Nam J, Choo H, Chong Y (2015). "Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors". Journal of Medicinal Chemistry. 58 (18): 7596–7602. doi:10.1021/acs.jmedchem.5b01263. PMID 26351728.
- ^ Clark, James D.; Flanagan, Mark E.; Telliez, Jean-Baptiste (2014-06-26). "Discovery and Development of Janus Kinase (JAK) Inhibitors for Inflammatory Diseases". Journal of Medicinal Chemistry. 57 (12): 5023–5038. doi:10.1021/jm401490p. ISSN 0022-2623. PMID 24417533.
- ^ Tan, Li; Akahane, Koshi; McNally, Randall; Reyskens, Kathleen M. S. E.; Ficarro, Scott B.; Liu, Suhu; Herter-Sprie, Grit S.; Koyama, Shohei; Pattison, Michael J. (2015-08-27). "Development of Selective Covalent Janus Kinase 3 Inhibitors". Journal of Medicinal Chemistry. 58 (16): 6589–6606. doi:10.1021/acs.jmedchem.5b00710. ISSN 0022-2623. PMC 4777322. 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 (in الإنجليزية). Retrieved 2017-09-26.
- ^ Vaddi K, Sarlis NJ, Gupta V (November 2012). "Ruxolitinib, an oral JAK1 and JAK2 inhibitor, in myelofibrosis". Expert Opinion on Pharmacotherapy. 13 (16): 2397–407. doi:10.1517/14656566.2012.732998. PMID 23051187. S2CID 29293800.
- ^ "Jakafi (ruxolitinib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Incyte Corporation. Wilmington, DE 19803. Retrieved 16 July 2016.
- ^ 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. PMID 22607178. 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. Retrieved 16 July 2016.
- ^ Gonzales AJ, Bowman JW, Fici GJ, Zhang M, Mann DW, Mitton-Fry M (August 2014). "Oclacitinib (APOQUEL(®)) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy". Journal of Veterinary Pharmacology and Therapeutics. 37 (4): 317–24. doi:10.1111/jvp.12101. PMC 4265276. PMID 24495176.
- ^ "FDA Approves Apoquel (oclacitinib tablet) to Control Itch and Inflammation in Allergic Dogs". Zoetis. 16 May 2013. Retrieved 23 February 2017.
- ^ "Apoquel (oclacitinib maleate tablet) Full Prescribing Information" (PDF). Zoetis Inc. Kalamazoo, MI 49007. Retrieved 23 February 2017.
- ^ "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. Retrieved 21 August 2018.
- ^ Kivitz AJ, Gutierrez-Ureña SR, Poiley J, Genovese MC, Kristy R, Shay K, Wang X, Garg JP, Zubrzycka-Sienkiewicz A (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. 69 (4): 709–719. doi:10.1002/art.39955. PMID 27748083.
- ^ Genovese MC, Greenwald M, Codding C, Zubrzycka-Sienkiewicz A, Kivitz AJ, Wang A, Shay K, Wang X, Garg JP, Cardiel MH (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. 69 (5): 932–942. doi:10.1002/art.40054. PMID 28118538.
- ^ Markham A, Keam SJ (June 2019). "Peficitinib: First Global Approval". Drugs. 79 (8): 887–891. doi:10.1007/s40265-019-01131-y. PMID 31093950. S2CID 155093525.
- ^ "FDA approves treatment for patients with rare bone marrow disorder". FDA (in الإنجليزية). 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". ir.celgene.com. Retrieved 16 August 2019.
- ^ "AbbVie Receives FDA Approval of RINVOQ™ (upadacitinib), an Oral JAK Inhibitor For The Treatment of Moderate to Severe Rheumatoid Arthritis | AbbVie News Center". news.abbvie.com (in الإنجليزية). Retrieved 16 August 2019.
- ^ "Clinical Trials with GLPG0634". ClinicalTrials.gov. Retrieved 16 July 2016.
- ^ Dhillon, Sohita (2020). "Delgocitinib: First Approval". Drugs. 80 (6): 609–615. doi:10.1007/s40265-020-01291-2. PMID 32166597. S2CID 212681247.
- ^ "Clinical Trials with PF04965842". ClinicalTrials.gov. Retrieved 21 May 2017.
- ^ "Abrocitinib (PF-04965842)". MedChemExpress. Retrieved November 21, 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. You must specify the date the archive was made using the
|archivedate=parameter. https://clinicaltrials.gov/ct2/show/NCT03349060. Retrieved on November 21, 2019. - ^ Liu D, Mamorska-Dyga A (July 2017). "Syk inhibitors in clinical development for hematological malignancies". Journal of Hematology & Oncology. 10 (1): 145. doi:10.1186/s13045-017-0512-1. PMC 5534090. PMID 28754125.
{{cite journal}}: CS1 maint: unflagged free DOI (link) - ^ "Clinical trials with LY2784544 (Gandotinib)". ClinicalTrials.gov. Retrieved 16 July 2016.
- ^ 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. PMID 20141349. 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. Retrieved 16 July 2016.
- ^ "Momelotinib Combined with Capecitabine and Oxaliplatin in Adults with Relapsed/Refractory Metastatic Pancreatic Ductal Adenocarcinoma". ClinicalTrials.gov. Retrieved 16 July 2016.
- ^ Hart S, Goh KC, Novotny-Diermayr V, Hu CY, Hentze H, Tan YC, Madan B, Amalini C, Loh YK, Ong LC, William AD, Lee A, Poulsen A, Jayaraman R, Ong KH, Ethirajulu K, Dymock BW, Wood JW (November 2011). "SB1518, a novel macrocyclic pyrimidine-based JAK2 inhibitor for the treatment of myeloid and lymphoid malignancies". Leukemia. 25 (11): 1751–9. doi:10.1038/leu.2011.148. PMID 21691275.
- ^ "Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis with Thrombocytopenia". ClinicalTrials.gov. 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. Retrieved 16 July 2016.
- ^ "BMS-986165 Phase 2, 3". ClinicalTrials.gov. Retrieved 29 July 2020.
- ^ Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM (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. 63 (6): 1270–9. PMID 12649187.
- ^ Meyer SC, Keller MD, Chiu S, Koppikar P, Guryanova OA, Rapaport F, et al. (July 2015). "CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative Neoplasms". Cancer Cell. 28 (1): 15–28. doi:10.1016/j.ccell.2015.06.006. PMC 4503933. PMID 26175413.
- ^ Stallard, J (23 July 2015). "Discovery Could Boost New Therapies for Myeloproliferative Neoplasms". Memorial Sloan Kettering Cancer Center. Retrieved 16 July 2016.
- ^ Gershon, E (19 June 2014). "In Hairless Man, Arthritis Drug Spurs Hair Growth — Lots of It". Yale News. Retrieved 16 July 2016.
- ^ Harel S, Higgins CA, Cerise JE, Dai Z, Chen JC, Clynes R, Christiano AM (October 2015). "Pharmacologic inhibition of JAK-STAT signaling promotes hair growth". Science Advances. 1 (9): e1500973. Bibcode:2015SciA....1E0973H. doi:10.1126/sciadv.1500973. PMC 4646834. PMID 26601320.