Janus kinase inhibitor

Janus kinase inhibitors, also known as JAK inhibitors or jakinibs,[1] are a type of medication that functions by inhibiting 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. These inhibitors have therapeutic application in the treatment of cancer and inflammatory diseases[1][2] such as rheumatoid arthritis.[3]

Mechanism of action

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.

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]

Molecule design

Some JAK1 inhibitors are based on a benzimidazole core.[4]

Examples

Approved

In clinical trials

Experimental

References

  1. 1 2 3 4 Kontzias A, Kotlyar A, Laurence A, Changelian P, O'Shea JJ (Aug 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.
  2. ↑ Pesu M, Laurence A, Kishore N, Zwillich SH, Chan G, O'Shea JJ (Jun 2008). "Therapeutic targeting of Janus kinases". Immunological Reviews 223: 132–42. doi:10.1111/j.1600-065X.2008.00644.x. PMC 2634846. PMID 18613833.
  3. ↑ Selective JAK inhibitors in development for rheumatoid arthritis. Norman 2014
  4. ↑ Benzimidazole Derivatives as Potent JAK1-Selective Inhibitors. Kim et al. 2015
  5. ↑ Vaddi K, Sarlis NJ, Gupta V (Nov 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.
  6. ↑ "Ruxolitinib (Jakafi) for myelofibrosis". The Medical Letter on Drugs and Therapeutics 54 (1387): 27–8. Apr 2012. PMID 22469651.
  7. ↑ Ostojic A, Vrhovac R, Verstovsek S (Nov 2011). "Ruxolitinib for the treatment of myelofibrosis". Drugs of Today (Barcelona, Spain : 1998) 47 (11): 817–27. doi:10.1358/dot.2011.47.11.1708829. PMID 22146225.
  8. ↑ Mesa RA, Yasothan U, Kirkpatrick P (Feb 2012). "Ruxolitinib". Nature Reviews. Drug Discovery 11 (2): 103–4. doi:10.1038/nrd3652. PMID 22293561.
  9. ↑ Product Information: JAKAFI(R) oral tablets, ruxolitinib oral tablets. Incyte Corporation (per manufacturer), Wilmington, DE, 2014
  10. ↑ 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.
  11. ↑ Product Information: XELJANZ(R) oral tablets, tofacitinib oral tablets. Pfizer Labs (per FDA), New York, NY, 2014.
  12. ↑ ABT494 shows structure
  13. ↑ "AbbVie Launches Phase 3 Trial for Rheumatoid Arthritis". Rheumatoid Arthritis News. 2016-01-29.
  14. ↑ "Incyte Earns $19M Milestone from Lilly on Start of Phase IIb Trial with RA Candidate". Genetic Engineering & Biotechnology News. 2010-10-20.
  15. ↑ "Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET)". ClinicalTrials.gov. U.S. National Institutes of Health. 2012-03-09.
  16. ↑ Pardanani A, Lasho T, Smith G, Burns CJ, Fantino E, Tefferi A (Aug 2009). "CYT387, a selective JAK1/JAK2 inhibitor: in vitro assessment of kinase selectivity and preclinical studies using cell lines and primary cells from polycythemia vera patients". Leukemia 23 (8): 1441–5. doi:10.1038/leu.2009.50. PMID 19295546.
  17. ↑ GLPG0634 at clinicaltrials.gov
  18. ↑ Shabbir M, Stuart R (Mar 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.
  19. ↑ 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 (Nov 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.
  20. ↑ "A Phase 1/2 Study of Oral SB1518 in Subjects With Chronic Idiopathic Myelofibrosis". ClinicalTrials.gov. U.S. National Institutes of Health. 2012-04-19.
  21. ↑ Blaskovich MA, Sun J, Cantor A, Turkson J, Jove R, Sebti SM (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 Res. 63 (6): 1270–9. PMID 12649187.
  22. ↑ https://www.mskcc.org/blog/discovery-could-boost-new-therapies-myeloproliferative-neoplasms-01
  23. ↑ http://news.yale.edu/2014/06/19/hairless-man-arthritis-drug-spurs-hair-growth-lots-it
  24. ↑ http://advances.sciencemag.org/content/1/9/e1500973.full
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