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]
Contents
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]
Examples
Approved
- Ruxolitinib against JAK1/JAK2 for psoriasis, myelofibrosis,[3][4][5] and rheumatoid arthritis.[6] Approved by the U.S. Food and Drug Administration (FDA) in November 2011 for myelofibrosis, intermediate- or high-risk and polycythemia vera, in patients with an inadequate response or intolerance to hydroxyurea.[7]
- Tofacitinib (tasocitinib; CP-690550) against JAK3 for psoriasis and rheumatoid arthritis.[8] US FDA approved in November 2012 for rheumatoid arthritis (moderate to severe), in patients who had an inadequate response or intolerance to methotrexate.[9]
In clinical trials
- Baricitinib (LY3009104, INCB28050) against JAK1/JAK2 starting phase IIb for rheumatoid arthritis[10]
- CYT387 against JAK2 for myeloproliferative disorders[11][12]
- Filgotinib (GLPG0634) against JAK1 for RA and Crohn's disease[13]
- Lestaurtinib against JAK2, for acute myelogenous leukemia (AML)[14]
- Pacritinib (SB1518) against JAK2 for relapsed lymphoma and advanced myeloid malignancies,[15] chronic idiopathic myelofibrosis (CIMF)[16]
Experimental
- JSI-124[17]
- CHZ868 (for use against myeloproliferative disorders and chronic myelomonocytic leukemia[18]
- Tofacitinib against JAK3 for alopecia universalis [19]
- Topical Tofacitinib and Ruxolitinib for alopecia [20]
References
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- ↑ Product Information: JAKAFI(R) oral tablets, ruxolitinib oral tablets. Incyte Corporation (per manufacturer), Wilmington, DE, 2014
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- ↑ Product Information: XELJANZ(R) oral tablets, tofacitinib oral tablets. Pfizer Labs (per FDA), New York, NY, 2014.
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- ↑ GLPG0634 at clinicaltrials.gov
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- ↑ https://www.mskcc.org/blog/discovery-could-boost-new-therapies-myeloproliferative-neoplasms-01
- ↑ http://news.yale.edu/2014/06/19/hairless-man-arthritis-drug-spurs-hair-growth-lots-it
- ↑ http://advances.sciencemag.org/content/1/9/e1500973.full
