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] There is interest in their use for various skin conditions.[4] JAK3 inhibitors are attractive as a possible treatment of various autoimmune diseases since its functions is mainly restricted to lymphocytes. Development for a selective JAK3 inhibitors are ongoing.[5]

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.[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]

Molecule design

Some JAK1 inhibitors are based on a benzimidazole core.[7]

Examples

Approved compounds
  • Ruxolitinib (trade names Jakafi/Jakavi) against JAK1/JAK2, for myelofibrosis and polycythemia vera[8] 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.[9]
  • Tofacitinib (trade names Xeljanz/Jakvinus, formerly known as tasocitinib and CP-690550) against JAK3 for psoriasis and rheumatoid arthritis.[10] 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.[11]
  • Oclacitinib (trade name Apoquel) — against JAK1[12] for the control of pruritus associated with allergic dermatitis and the control of atopic dermatitis in dogs at least 12 months of age.[13][14]
  • Baricitinib (trade name Olumiant) against JAK1/JAK2 for rheumatoid arthritis.[15]
  • Peficitinib (ASP015K, JNJ-54781532; trade name Smyraf) mainly inhibits JAK3 and used for treatment of rheumatoid arthritis.[16][17] Approved for use in Japan in 2019.[18]
  • 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.[19][20]
  • Upadacitinib (trade name Rinvoq; ABT-494) against JAK1 for rheumatoid arthritis. Approved by U.S FDA on 16 August 2019.[21]

In clinical trials

Experimental drugs/indications
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References
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