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 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 (since they were just two of many discoveries ...

family of enzymes ( JAK1,

JAK2 Janus kinase 2 (commonly called JAK2) is a non-receptor tyrosine kinase. It is a member of the Janus kinase family and has been implicated in signaling by members of the type II cytokine receptor family (e.g. interferon receptors), the GM-CSF rece ...

, JAK3,

TYK2 Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the ''TYK2'' gene. Tyk2 was the first member of the JAK family that was described (the other members are JAK1, JAK2, and JAK3). It has been implicated in IFN-α ...

), thereby interfering with the

JAK-STAT signaling pathway 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 ou ...

in lymphocytes. It is used in the treatment of cancer and

inflammatory disease Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

s such as

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are invol ...

and various skin conditions.A

Janus kinase 3 inhibitor 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-prote ...

is attractive as a possible treatment of various autoimmune diseases since its function is mainly restricted to

lymphocyte A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...

s. As of 2017, development of a selective JAK3 inhibitor was ongoing.

Contraindications

The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(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. 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 alternative treatments 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. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. 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 Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...

(VTE)) other than those listed above. The special warnings by FDA and EMA are important for shared-decision making with the patient.

Mechanism of action

Janus kinase inhibitors can be classed in several overlapping classes: they are

immunomodulator Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...

s, they are DMARDs (

disease-modifying antirheumatic drug Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroida ...

s), and they are a subclass of

tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...

s. They work by modifying the

immune system The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...

via

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

activity inhibition.

Cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s play key roles in controlling cell growth and the

immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of different microorganisms including viruses, bacteria, parasites, and fungi which could ...

. Many cytokines function by binding to and activating

type I cytokine receptor Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands. These receptors are also known under the name ''hemopoietin receptors'', and share a c ...

s and type II cytokine receptors. These receptors in turn rely on the

(JAK) family of enzymes for signal transduction. Hence drugs that inhibit the activity of these Janus kinases block cytokine signalling. More specifically, Janus kinases

phosphorylate In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...

activated cytokine receptors. These phosphorylated receptors in turn recruit

STAT STAT, Stat. , or stat may refer to: * Stat (system call), a Unix system call that returns file attributes of an inode * ''Stat'' (TV series), an American sitcom that aired in 1991 * Stat (website), a health-oriented news website * STAT protein, a ...

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...

s which modulate gene transcription. The first JAK inhibitor to reach clinical trials was

tofacitinib Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. Common side effects include diarrhea, headache, and high blood pressure. Serious side eff ...

. Tofacitinib is a specific inhibitor of JAK3 ( IC₅₀ = 2 nM) thereby blocking the activity of

IL-2 The Ilyushin Il-2 (Russian: Илью́шин Ил-2) is a ground-attack plane that was produced by the Soviet Union in large numbers during the Second World War. The word ''shturmovík'' ( Cyrillic: штурмовик), the generic Russian term ...

, IL-4, IL-15 and IL-21. Hence T_h2 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

(IC₅₀ = 20 nM), which in turn blocks

IFN-γ Interferon gamma (IFN-γ) is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock ...

and IL-6 signalling and consequently T_h1 cell differentiation. One mechanism (relevant to psoriasis) is that the blocking of Jak-dependent IL-23 reduces IL-17 and the damage it causes.

Molecule design

Some JAK1 inhibitors are based on a

benzimidazole Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a colorless solid. Preparation Benzimidazole is produced by condensation of o ...

core. 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. Another ring system that has been used in JAK3 inhibitor derivatives is 1H-pyrrolo ,3-byridine, as it mimics the pyrrolopyrimidine scaffold. More information on the structure activity relationship of may be found in the article on JAK3 inhibitors.

Examples

Approved compounds

In clinical trials

Cerdulatinib Cerdulatinib is a small molecule SYK/JAK kinase inhibitor in development for treatment of hematological malignancies. It has lowest nM IC50 values against TYK2, JAK1, JAK2, JAK3, FMS, and SYK. It is being developed by Portola Pharmaceutical ...

(PRT062070) dual SYK/JAK inhibitor for hematological malignancies. * Gandotinib (LY-2784544) against JAK2 for

myeloproliferative neoplasm Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. ''Myelo'' refers to the bone marrow, ''proliferative'' describes the rapid growt ...

s. *

Lestaurtinib Lestaurtinib ( rINN, codenamed CEP-701) is a tyrosine kinase inhibitor structurally related to staurosporine. This semisynthetic derivative of the indolocarbazole K252a was investigated by Cephalon as a treatment for various types of cancer. It ...

(CEP-701) against JAK2 for

acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with normal blood cell production. Symptoms may inclu ...

(AML). * Momelotinib (GS-0387, CYT-387) against JAK1 and JAK2 for myeloproliferative disorders and relapsed/refractory metastatic pancreatic cancer. * Pacritinib (SB1518) for relapsed

lymphoma Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enla ...

and advanced myeloid malignancies, also myelofibrosis, myeloproliferative neoplasms and

myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which immature blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may ...

. * Deucravacitinib is currently in clinical trials for

psoriatic arthritis Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. Th ...

, inflammatory bowel disease and systemic lupus erythematosus.

Experimental drugs/indications

* Cucurbitacin I (JSI-124). * CHZ868 — a type II JAK2 inhibitor for use in myeloproliferative disorders and

chronic myelomonocytic leukemia Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are i ...

(CMML). * Tofacitinib for

alopecia universalis __NOTOC__ Alopecia universalis (AU), also known as alopecia areata universalis, is a medical condition involving the loss of all body hair, including eyebrows, eyelashes, chest hair, armpit hair, and pubic hair. It is the most severe form of alop ...

. * Topical tofacitinib and ruxolitinib for

alopecia Hair loss, also known as alopecia or baldness, refers to a loss of hair from part of the head or body. Typically at least the head is involved. The severity of hair loss can vary from a small area to the entire body. Inflammation or scar ...

References

External links

{{DEFAULTSORT:Janus Kinase Inhibitor Non-receptor tyrosine kinase inhibitors