Janus kinases (JAKs) constitute a family of intracellular, non-receptor tyrosine kinases
- is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2
- are associated with their corresponding cell surface receptors and transduce signals from cytokines, as well as some hormones, such as growth hormone and prolactin
- JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions (1)
- JAK1 seems to play a role in conditions such as:
- pruritic dermatitis
- allergic rhinitis
- asthma
- inflammatory bowel disease
- inhibition of JAK1 and JAK2 molecules with JAK1 and JAK2 inhibitory activity have also provided therapeutic benefits in the treatment of:
- rheumatoid arthritis
- psoriasis
- pruritis
- inhibition of JAK3 several JAK3 selective inhibitors have been evaluated for their efficacy in the treatment of rheumatoid arthritis
- TYK2 selective inhibitors may also be useful in the treatment of autoimmune diseases
JAK/STAT signaling in the pathogenesis of the myeloproliferative neoplasms (MPNs)
A central role for JAK/STAT signaling in the pathogenesis of the myeloproliferative neoplasms (MPNs) was discovered by identifying the somatically acquired JAK2V617F mutation in more than 95% of patients with polycythemia vera (PV) and over 50% of patients with essential thrombocytosis and primary myelofibrosis (2,3,4)
- JAK2 V617F mutation is an acquired, somatic mutation present in the majority of patients with myeloproliferative cancer
- the JAK2 V617F mutation may also be prevalent in individuals without overt signs of myeloproliferative cancer
- activated JAK2 signaling by JAK2, CALR, and MPL mutations has become a focus for the development of targeted therapies for patients with MPN (3)
- JAK2 inhibitors now represent a standard of clinical care for certain forms of MPN and offer important benefits for MPN patients
Reference:
- Nielsen C, Birgens HS, Nordestgaard BG, Kjaer L, Bojesen SE. The JAK2 V617F somatic mutation, mortality and cancer risk in the general population. Haematologica. 2011 Mar;96(3):450-3
- Bader MS, Meyer SC. JAK2 in Myeloproliferative Neoplasms: Still a Protagonist. Pharmaceuticals (Basel). 2022 Jan 28;15(2):160. doi: 10.3390/ph15020160. PMID: 35215273; PMCID: PMC8874480.
- Schieber M, Crispino JD, Stein B. Myelofibrosis in 2019: moving beyond JAK2 inhibition. Blood Cancer J. 2019 Sep 11;9(9):74. doi: 10.1038/s41408-019-0236-2. PMID: 31511492; PMCID: PMC6739355.
- Shawky AM, Almalki FA, Abdalla AN, Abdelazeem AH, Gouda AM. A Comprehensive Overview of Globally Approved JAK Inhibitors. Pharmaceutics. 2022 May 6;14(5):1001