Janus kinase inhibitor

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib,[1] is a type of immune modulating medication, which inhibits 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 in lymphocytes.

It is used in the treatment of cancer and inflammatory diseases[1][2] such as rheumatoid arthritis[3] and various skin conditions.[4]A Janus kinase 3 inhibitor is attractive as a possible treatment of various autoimmune diseases since its functions is mainly restricted to lymphocytes. As of 2017, development for a selective JAK3 inhibitor was ongoing.[5]

Contraindications

The US Food and Drug Administration (FDA) requires the boxed warning for tofacitinib, baricitinib, and upadacitinib to include information about the risks of serious heart-related events, cancer, blood clots, and death.[6][7]

The Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA) recommends that the Janus kinase inhibitors abrocitinib, filgotinib, baricitinib, upadacitinib, and tofacitinib should be used in the following people only if no suitable treatment alternatives are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past and those at increased risk of cancer.[8][9] The committee also recommends using JAK inhibitors with caution in people with risk factors for blood clots in the lungs and in deep veins (venous thromboembolism (VTE)) other than those listed above.[8]

Mechanism of action

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 cytokine receptors 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.[10]

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.[11]

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.[12][13] Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo[2,3-b]pyridine, as it mimics the pyrrolopyrimidine scaffold.[14] More information on the structure activity relationship of may be found in the article on JAK3 inhibitors.

Examples

Approved compounds
DrugBrand nameSelectivityApproval dateIndicationsReferences
Ruxolitinib (oral)Jakafi, JakaviJAK1, JAK2November 2011 (U.S.)
July 2012 (Europe)
July 2014 (Japan)		 [15][16]
TofacitinibXeljanz, Xeljanz XR, JaquinusJAK1, JAK2, JAK3November 2012 (U.S.)
March 2013 (Japan)
March 2017 (Europe)

Indicated in intolerance or inefficacy of TNF inhibitors or DMARDs, or other conventional therapy or biologic agents

 [17][18]
OclacitinibApoquelJAK1May 2013 (U.S.) [19][20][21]
BaricitinibOlumiantJAK1, JAK2February 2017 (Europe)
July 2017 (Japan)
May 2018 (U.S.)		 [22][23]
PeficitinibSmyrafJAK1, JAK3March 2019 (Japan)
January 2020 (South Korea)		 [24][25][26]
UpadacitinibRinvoqJAK1August 2019 (U.S.)
November 2019 (Japan)
December 2019 (Europe)

Indicated in intolerance or inefficacy of TNF inhibitors or DMARDs, or other conventional therapy or biologic agents

 [27]
FedratinibInrebicJAK2August 2019 (U.S.)
February 2021 (Europe)
  • Primary and secondary myelofibrosis (intermediate-2 or high-risk)
 [28][29]
Delgocitinib (topical)CorectimNon-selectiveJanuary 2020 (Japan) [30]
FilgotinibJyselecaJAK1September 2020 (Europe, Japan)

Indicated in intolerance or inefficacy of DMARDs or conventional therapy

 [31]
AbrocitinibCibinqoJAK1September 2021 (Japan)
December 2021 (Europe)
January 2022 (U.S.)
  • Refractory moderate-to-severe atopic dermatitis with inadequate response to other systemic therapy
 [32][33][34]
Ruxolitinib (topical)OpzeluraJAK1, JAK2September 2021 (U.S.) [35]
PacritinibVonjoJAK2February 2022 (U.S.) [36]
DeucravacitinibSotyktuTYK2September 2022 (U.S.) [37]

In clinical trials

Experimental drugs/indications

References
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