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]


Approved compounds

In clinical trials

Experimental drugs

Failed agents


  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 3419278Freely accessible. 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 2634846Freely accessible. 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 (10 October 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. 2 April 2012. PMID 22469651.
  7. Ostojic, A; Vrhovac, R; Verstovsek, S (November 2011). "Ruxolitinib for the Treatment of Myelofibrosis". Drugs of Today. 47 (11): 817–27. doi:10.1358/dot.2011.47.11.1708829. PMID 22146225.
  8. Mesa, RA; Yasothan, U; Kirkpatrick, P (1 February 2012). "Ruxolitinib". Nature Reviews. Drug Discovery. 11 (2): 103–4. doi:10.1038/nrd3652. PMID 22293561.
  9. "Jakafi (ruxolitinib) Tablets, for Oral Use. Full Prescribing Information" (PDF). Incyte Corporation. Wilmington, DE 19803. Retrieved 16 July 2016.
  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. "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.
  12. "Incyte Earns $19M Milestone from Lilly on Start of Phase IIb Trial with RA Candidate". GEN. Genetic Engineering & Biotechnology News. 20 October 2010. Retrieved 16 July 2016.
  13. "Clinical Trials with GLPG0634". ClinicalTrials.gov. Retrieved 16 July 2016.
  14. "Clinical trials with LY2784544 (Gandotinib)". ClinicalTrials.gov. Retrieved 16 July 2016.
  15. 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.
  16. "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.
  17. "Momelotinib Combined with Capecitabine and Oxaliplatin in Adults with Relapsed/Refractory Metastatic Pancreatic Ductal Adenocarcinoma". ClinicalTrials.gov. Retrieved 16 July 2016.
  18. 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" (PDF). Leukemia. 25 (11): 1751–9. doi:10.1038/leu.2011.148. PMID 21691275. Retrieved 16 July 2016.
  19. "Oral Pacritinib Versus Best Available Therapy to Treat Myelofibrosis with Thrombocytopenia". ClinicalTrials.gov. Retrieved 16 July 2016.
  20. "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.
  21. Henriques, C (29 January 2016). "AbbVie Launches Phase 3 Trial for Rheumatoid Arthritis". Rheumatoid Arthritis News. BioNews Services, LLC. Retrieved 16 July 2016.
  22. Blaskovich, MA; Sun, J; Cantor, A; Turkson, J; Jove, R; Sebti, SM (15 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. Retrieved 16 July 2016.
  23. Meyer, SC; Keller, MD; Chiu, S; Koppikar, P; Guryanova, OA; Rapaport, F; Xu, K; Manova, K; Pankov, D; O'Reilly, RJ; Kleppe, M; McKenney, AS; Shih, AH; Shank, K; Ahn, J; Papalexi, E; Spitzer, B; Socci, N; Viale, A; Mandon, E; Ebel, N; Andraos, R; Rubert, J; Dammassa, E; Romanet, V; Dölemeyer, A; Zender, M; Heinlein, M; Rampal, R; Weinberg, RS; Hoffman, R; Sellers, WR; Hofmann, F; Murakami, M; Baffert, F; Gaul, C; Radimerski, T; Levine, RL (13 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 4503933Freely accessible. PMID 26175413.
  24. Stallard, J (23 July 2015). "Discovery Could Boost New Therapies for Myeloproliferative Neoplasms". Memorial Sloan Kettering Cancer Center. Retrieved 16 July 2016.
  25. Gershon, E (19 June 2014). "In Hairless Man, Arthritis Drug Spurs Hair Growth — Lots of It". Yale News. Retrieved 16 July 2016.
  26. Harel, S; Higgins, CA; Cerise, JE; Dai, Z; Chen, JC; Clynes, R; Christiano, AM (23 October 2015). "Pharmacologic Inhibition of JAK-STAT Signaling Promotes Hair Growth". Science Advances. 1 (9): e1500973. doi:10.1126/sciadv.1500973. PMC 4646834Freely accessible.
  27. "Sanofi Discontinues Clinical Development of Investigational JAK2 Agent Fedratinib (SAR302503)" (PDF). Sanofi Oncology. Retrieved 16 July 2016.
This article is issued from Wikipedia - version of the 7/16/2016. The text is available under the Creative Commons Attribution/Share Alike but additional terms may apply for the media files.