Janus kinase 3 inhibitor

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Janus kinase 3 inhibitors, also called JAK3 inhibitors, are a new class of immunomodulatory agents that inhibit Janus kinase 3. They are used for the treatment of autoimmune diseases. The Janus kinases are a family of four nonreceptor tyrosine-protein kinases, JAK1, JAK2, JAK3, and TYK2. They signal via the JAK/STAT pathway, which is important in regulating the immune system. [1] Expression of JAK3 is largely restricted to lymphocytes (predominant expression is in the hematopoietic system), while the others are ubiquitously expressed, so selective targeting of JAK3 over the other JAK isozymes is attractive as a possible treatment of autoimmune diseases. [2] [3]

Contents

Activation of JAK3 by cytokine receptors that contain the common gamma chain (gc) JAK3 signal transduction.jpg
Activation of JAK3 by cytokine receptors that contain the common gamma chain (γc)

Mechanism of action

Janus kinase 3 inhibitors work by inhibiting the action of the enzyme Janus kinase 3, thereby interfering with the JAK-STAT signaling pathway. JAK3 is required for signaling by cytokines through the common γ chain of the interleukin receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. [4] However, JAK1 is also required as the two kinases cooperate for signaling. [5] This signaling process leads to phosphorylation and dimerization of the adaptor proteins STAT. When activated, they translocate into the nucleus, where they modulate gene transcription. [6] By selectively inhibiting JAK3, downward signaling can be blocked.

JAK3 is crucial in transmitting signals from cytokines that are responsible for either T-cell proliferation, differentiation, or development. It is also of high importance in the development of B-cells and NK-cells. [7] Inhibition of JAK3, then, could prove to be a powerful immunosuppressant. Since JAK3 is restricted to the immune system, while the other JAKs such as JAK1 are much more broadly expressed, selective targeting of JAK3 could decrease possible adverse effects and improve tolerability. [2] [1]

As an immunosuppressant, JAK3 inhibitors could aid in autoimmune diseases such as rheumatoid arthritis, psoriasis, or other diseases where the immune system fails to distinguish self from nonself and starts attacking self cells. [8] [9]

Discovery and development

Discovery

One of the first JAKs targeted in drug development for medical use was JAK3. Immune system depression is observed in patients with JAK3 defects. The role of JAK3 is greatly restricted to the immune system, so this enzyme was thought to be a good target for selective immunosuppressant. [10] [3] Whether JAK3 alone is sufficient to suppress cytokine signaling is uncertain, as it can also be caused by stimulation of JAK1. Whether inhibiting JAK3 is as efficient as pan-JAK inhibition is under study. [5] [11] Many compounds with high affinity and possible selectivity for JAK3 have been discovered with high-throughput screening. [4]

Development

Currently, much attention is focused on developing Janus kinase inhibitors as drugs for immune diseases including inflammatory bowel diseases, rheumatoid arthritis, alopecia areata, and psoriases. [12]

The first JAK inhibitor approved for the treatment of rheumatoid arthritis was tofacitinib. It has also shown promising results in other autoimmune disorders. [13] [1] Initially, tofacitinib was thought to be a selective JAK3 inhibitor, but later was found to be a potent inhibitor of JAK1 and JAK2. [2] The value of developing a selective JAK3 targeting over the other JAKs is that JAK3 expression is restricted to the immune system, while the other JAKs are much more broadly expressed. [1] Since JAK3 is not as ubiquitously expressed, selective targeting could improve tolerability, and decrease possible adverse effects and safety concerns. [2] For example, dual inhibition of JAK1 and JAK3 might increase bacterial and viral infection because of a broader immunosuppressive effect. Inhibition of JAK2 has been linked to adverse effects such as anaemia and generalised leukopenia. [10]

Common structure groups of ATP and inhibitors that target the ATP binding site on JAK3. JanusKinas3-WIKI.png
Common structure groups of ATP and inhibitors that target the ATP binding site on JAK3.

Developing sufficiently selective JAK3 inhibitors has been difficult. One of the reason is the small variation in the ATP binding site of different JAKs. Another problem is that JAK3 has a higher affinity for ATP than the other JAKs, which can be a reason for a poor translation from in vitro enzymatic assay studies to cellular system studies. [3] An example of this is decernotinib, which showed 41-fold selectivity for JAK3 vs JAK1 in in vitro enzyme assays, while the selectivity for JAK3 was not maintained in cellular assays, where it showed a slight preference for JAK1. [11] [14]

Structure activity relationship

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. [15] [1] Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo[2,3-b]pyridine, as it mimics the pyrrolopyrimidine scaffold. [16]

Sequence alignment has shown that the ATP binding pockets of the JAKs are almost identical and only a few features distinguish JAK3 from the rest. One of these differences is the presence of cysteine residue (Cys909) in the front region of the ATP binding pocket, where the other JAKs have serine at that same position. [1] [17] Only 10 other kinases possess a cysteine at that location, making cysteine even more intriguing as a target for a better selectivity. [18] The focus has been on structures that can react with cysteine and have the electrophilic warhead acrylamide have been of interest, as they should ideally react only with proximal cysteine. [19] [11] Covalent cysteine targeting can be tricky, as off-target reaction can lead to adverse reactions, but as the JAKs resynthesize rapidly, covalent inhibition could be necessary to extend the pharmacodynamics. [20] [3]

To compare inhibitors, the parameter of choice is IC50; by measuring IC50 for different JAKs, determining selectivity is possible. In the kinase family, JAK3 has the highest affinity for ATP, so measuring IC50 in high concentrations of ATP show whether the inhibitor can compete with ATP for the binding site. [3]

Medical use

Several therapeutic options exist for the treatment of autoimmune diseases, but the search is still going on for safer, more effective, and more convenient treatments. Inhibition of JAK3 has in research shown to be a good target for immunosuppression. [2]

The only indication for a JAK3 inhibitor at the moment, rheumatoid arthritis, is for the nonselective JAK1/JAK3 inhibitor tofacitinib. [18] Other indications, such as psoriasis, alopecia areata, and ulcerative colitis are in clinical trials. Cytokines have an important role in autoimmune diseases and as the common γ chain cytokines interleukin IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 signal via JAK3, the inhibition of JAK3 and blocking of the signaling of these cytokines could affect many immune diseases and lead to development of new effective immunosuppressive drugs. [2]

List of JAK3 inhibitors

Nonselective JAK3 inhibitor

JAK3 inhibitors in clinical trials

Related Research Articles

Janus kinase (JAK) is a family of intracellular, non-receptor tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway. They were initially named "just another kinase" 1 and 2, but were ultimately published as "Janus kinase". The name is taken from the two-faced Roman god of beginnings, endings and duality, Janus, because the JAKs possess two near-identical phosphate-transferring domains. One domain exhibits the kinase activity, while the other negatively regulates the kinase activity of the first.

The JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumour formation. The pathway communicates information from chemical signals outside of a cell to the cell nucleus, resulting in the activation of genes through the process of transcription. There are three key parts of JAK-STAT signalling: Janus kinases (JAKs), signal transducer and activator of transcription proteins (STATs), and receptors. Disrupted JAK-STAT signalling may lead to a variety of diseases, such as skin conditions, cancers, and disorders affecting the immune system.

<span class="mw-page-title-main">IL-2 receptor</span> Lymphocyte receptor specific for Interleukin-2

The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2.

<span class="mw-page-title-main">Tyrosine kinase 2</span> Enzyme and coding gene in humans

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.

<span class="mw-page-title-main">Janus kinase 3</span> Mammalian protein found in Homo sapiens

Tyrosine-protein kinase JAK3 is a tyrosine kinase enzyme that in humans is encoded by the JAK3 gene.

<span class="mw-page-title-main">Janus kinase 1</span>

JAK1 is a human tyrosine kinase protein essential for signaling for certain type I and type II cytokines. It interacts with the common gamma chain (γc) of type I cytokine receptors, to elicit signals from the IL-2 receptor family, the IL-4 receptor family, the gp130 receptor family. It is also important for transducing a signal by type I (IFN-α/β) and type II (IFN-γ) interferons, and members of the IL-10 family via type II cytokine receptors. Jak1 plays a critical role in initiating responses to multiple major cytokine receptor families. Loss of Jak1 is lethal in neonatal mice, possibly due to difficulties suckling. Expression of JAK1 in cancer cells enables individual cells to contract, potentially allowing them to escape their tumor and metastasize to other parts of the body.

<span class="mw-page-title-main">MAP3K7</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.

Interleukin 20 receptors (IL20R) belong to the IL-10 family. IL20R are involved in both pro-inflammatory and anti-inflammatory immune response. There are two types of IL20R: Type I and Type II.

<span class="mw-page-title-main">John J. O'Shea</span> American physician and immunologist

John J. O'Shea is an American physician and immunologist.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

JAK3 deficiency is a dysfunction in cytokine receptor signalling and their production of cytokines.

<span class="mw-page-title-main">Tofacitinib</span> Medication

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis. It is a janus kinase (JAK) inhibitor, discovered and developed by the National Institutes of Health and Pfizer.

<span class="mw-page-title-main">Filgotinib</span> Chemical compound

Filgotinib, sold under the brand name Jyseleca, is a medication used for the treatment of rheumatoid arthritis (RA). It was developed by the Belgian-Dutch biotech company Galapagos NV.

<span class="mw-page-title-main">Oclacitinib</span> Medication

Oclacitinib, sold under the brand name Apoquel among others, is a veterinary medication used in the control of atopic dermatitis and pruritus from allergic dermatitis in dogs at least 12 months of age. Chemically, it is a synthetic cyclohexylamino pyrrolopyrimidine janus kinase inhibitor that is relatively selective for JAK1. It inhibits signal transduction when the JAK is activated and thus helps downregulate expression of inflammatory cytokines.

<span class="mw-page-title-main">Upadacitinib</span> Chemical compound (medication)

Upadacitinib, sold under the brand name Rinvoq, is a medication used for the treatment of rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ulcerative colitis, Crohn's disease, ankylosing spondylitis, and axial spondyloarthritis. Upadacitinib is a Janus kinase (JAK) inhibitor that works by blocking the action of enzymes called Janus kinases. These enzymes are involved in setting up processes that lead to inflammation, and blocking their effect brings inflammation in the joints under control.

<span class="mw-page-title-main">Decernotinib</span> Chemical compound

Decernotinib is an inhibitor of Janus kinase 3 (JAK3) discovered through a process of inhouse screening of a chemical compound library. Decernotinib also had the name VX-509 in development phase. It is an experimental drug with high selectivity for JAK3, which demonstrates good efficacy in vivo in the rat host versus graft model (HvG). It has been studied in clinical trials at Vertex Pharmaceuticals, and while it was not approved for clinical use it continues to be used for research.

<span class="mw-page-title-main">Dapansutrile</span> Chemical compound

Dapansutrile (OLT1177) is an inhibitor of the NLRP3 inflammasome.

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

<span class="mw-page-title-main">Z583</span>

Z583 (GLXC-26150) is a chemical compound which acts as a potent and highly selective inhibitor of JAK3, and was developed for the treatment of rheumatoid arthritis.

<span class="mw-page-title-main">Izencitinib</span>

Izencitinib (TD-1473) is a drug which acts as a pan-Janus kinase inhibitor, binding with high affinity at all three subtypes JAK1, JAK2 and JAK3. It is taken orally and was developed to be gut selective with minimal absorption into the rest of the body, allowing targeting of inflammatory bowel disease but with reduced side effects compared to other similar drugs.

References

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  6. ↑ Imada, Kazuroni; Leonard, Warren J (2000-01-01). "The Jak-STAT pathway". Molecular Immunology. 37 (1): 1–11. doi:10.1016/S0161-5890(00)00018-3. PMID   10781830.
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  8. ↑ O’Shea, John J.; Kontzias, Apostolos; Yamaoka, Kunihiro; Tanaka, Yoshiya; Laurence, Arian (April 2013). "Janus kinase Inhibitors in autoimmune diseases". Annals of the Rheumatic Diseases. 72: ii111–ii115. doi:10.1136/annrheumdis-2012-202576. ISSN   0003-4967. PMC   3616338 . PMID   23532440.
  9. ↑ Wang, Lifeng; Wang, Fu-Sheng; Gershwin, M. Eric (2015-10-01). "Human autoimmune diseases: a comprehensive update". Journal of Internal Medicine. 278 (4): 369–395. doi: 10.1111/joim.12395 . ISSN   1365-2796. PMID   26212387.
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