Distribution of indications for JAK inhibitors .pdf
Original filename: Distribution of indications for JAK inhibitors.pdf
This PDF 1.7 document has been generated by Microsoft® Word 2016, and has been sent on pdf-archive.com on 03/03/2019 at 02:41, from IP address 42.244.x.x.
The current document download page has been viewed 438 times.
File size: 131 KB (4 pages).
Privacy: public file
Download original PDF file
Research and Development of Janus Kinase (JAK)
(This article first appeared on BOC Sciences’ Blog.)
Introduction of JAK-STAT signaling Pathway
The JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines,
which is involved in many important biological processes such as cell proliferation,
differentiation, apoptosis, and immune regulation. Compared with other signal pathways, this
signal pathway is relatively simple, it mainly consists of three components, namely tyrosine
kinase-related receptor, tyrosine kinase JAK and transcription factor STAT. JAK kinase
mediates signal transduction of most cytokines in cells. Such
as interleukin (IL), interferon (IFN), erythropoietin (EPO), granulocyte and macrophage
colony-stimulating factor (GM-CSF), growth-promoting factor (GH), prolactin
(PRL), thrombopoietin (TPO), Platelet-derived factor (PDGF) and epidermis Cell growth
factor (EGF), etc. Moreover, different receptors can activate different subtypes of JAK
kinases, thus showing different biological functions.
JAK kinase drug target
JAK kinase is a very important drug target, and JAK inhibitors developed for this target are
mainly used to screen drugs for the treatment of hematological diseases, tumors, rheumatoid
arthritis, and psoriasis. JAK-1, JAK-2, and TYK-2 were expressed in all tissues and cells of
the human body. JAK-3 was mainly expressed in hematopoietic tissue cells, mainly in bone
marrow cells, thymocytes, NK cells, activated B lymphocytes and T lymphocytes.
JAK1 binds to IL-10, IL-19, IL-20, IL-22, IL-26, IL-28, and IFN- α, IFN- γ, IL-6 in the gp130
family and other receptors containing γ c. JAK1 has become a new target in the field of
immunity, inflammation, and cancer.
JAK2 plays an important role in the regulation of many receptors, including EPO, GH, PRL,
IFN- γ and IL-3, IL-5, GM-CSF, a member of the β c family. A base mutation JAK2V617F,
which is closely related to the occurrence of polycythemia vera (PV) idiopathic thrombocytosis
(ET) idiopathic myelofibrosis (IMF) and chronic myelogenous leukemia (CML) in
myeloproliferative diseases. Therefore, JAK2 has become the exact target for the treatment
and prevention of this kind of disease.
JAK3 regulates cell signal transduction by binding to γ cochain (γ c) in cytokine receptor
complexes such as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Both JAK3 and γ c mutations can
lead to severe combined immunodeficiency. The abnormal activity of JAK3 is characterized
by the decrease of T and NK cells and the loss of function of B cells, which seriously affects
the normal biological functions of the immune system. Because of its functional
characteristics and special tissue distribution, JAK3 has become an attractive drug target for
immune system-related diseases.
TYK2 is the first member of JAK family, which can be activated by IFNs, IL-10, IL-6, IL-12, IL23, IL-27 and other receptors. In mice, TYK2 dysfunction can lead to a variety of cytokine
receptor signaling pathway defects, resulting in viral infection, decreased antibacterial
immune function and increased the possibility of pulmonary infection.
Distribution of indications for JAK inhibitors
The first JAK kinase was discovered in the early 1990s, and it was not until 2012 that the first
JAK kinase inhibitor-tofacitinib, was approved for the treatment of Rheumatoid arthritis (RA).
RA is a chronic systemic autoimmune disease characterized by joint disease, which is
characterized by persistent damage of the immune system to the joint and other tissues.
Complex diseases are mediated by a variety of immune cells (B lymphocytes, T lymphocytes,
macrophages, etc.) and related cytokines. Rheumatoid arthritis is known to cause a range of
symptoms, including pain and swelling in the joints, especially in the hands, feet, and knees.
Statistics show that there are about 4 million rheumatoid arthritis patients in China, the
remission rate of patients is 8.6%, and the disability rate is about 50.3%. At present, tofacitinib
is also used in a number of clinical studies with different indications, such as dry eye disease,
Crohn’s disease, psoriasis, ulcerative colitis, and organ transplantation.
JAK inhibitor development pipeline
At present, the JAK inhibitors approved by EMA for FDA
are Ruxolitinib, Tofacitinib, Oclacitinib, andBaricitinib.
Ruxolitinib, an inhibitor of JAK1 and JAK2, developed by Incyte and Novartis, was approved
by FDA in November 2011 and is the first drug approved specifically to treat myelofibrosis.
Ruxolitinib is conducting a number of clinical trials in the middle and late stages, indications
include a variety of cancers, rejection, alopecia areata, allergic dermatitis, rheumatoid
arthritis, vitiligo, psoriasis, and so on.
Tofacitinib, an inhibitor of JAK3 and JAK1 developed by Pfizer and approved by FDA in
November 2012. This is the first oral JAK inhibitor approved for RA therapy. Tofacitinib may
lead to some adverse reactions, including infection, tuberculosis, tumor and liver injury, and
some of these adverse reactions may be related to the lack of selectivity of tofacitinib to JAK3. The European Medicines Agency Council of Medicines for Human use (CHMP) has not
approved the drug for sale in Europe after considering the efficacy and adverse reactions of
the drug in the treatment of RA.
Oclacitinib, is a new JAK1 inhibitor approved by the FDA in 2013 to control itching and atopic
dermatitis caused by allergic dermatitis in dogs.
Baricitinib, is a selective inhibitor of JAK1 and JAK2. On Jan. 20, 2016, Incyte and its partner
Eli Lilly announced that baricitinib had submitted a NDA application for the treatment of mild
to severe rheumatoid arthritis. Clinical trials of the drug are currently underway for a number
of different indications.
When the development of JAK inhibitors was just beginning, based on the understanding of
the different biological functions of JAKs, the researchers predicted some characteristics of
JAK inhibitors. With the development of large-scale clinical trials of JAK inhibitors, some of
the original predictions have been confirmed, but some unexpected results have been
produced, and some key questions remain unanswered. For example, there are questions as
to what extent the selection performance of JAK inhibitors has been achieved, and is it really
advantageous to have high selectivity? Perhaps some of the uncertainties in the development
of JAK inhibitors will be resolved step by step as more new trial data become available.
1. Rawlings, J. S., Rosler, K. M., & Harrison, D. A. (2004). The JAK/STAT signaling
pathway. Journal of cell science, 117(8), 1281-1283.
2. Murray, P. J. (2007). The JAK-STAT signaling pathway: input and output integration. The
Journal of Immunology, 178(5), 2623-2629.
3. Yan, Z., Gibson, S. A., Buckley, J. A., Qin, H., & Benveniste, E. N. (2018). Role of the
JAK/STAT signaling pathway in regulation of innate immunity in neuroinflammatory
diseases. Clinical Immunology, 189, 4-13.