4.1 JAK inhibitors in clinical trials approved by FDA
Traced back to 2000th, the tyrosine kinase inhibitor
imatinib successed in the treatment of chronic myelogenous leukaemia.
Immediately followed by imatinib, dozens of kinase inhibitors were
approved for the treatment of various cancers. In 2011th, the first
JAKinib ruxolitinib targeting JAK2 was designed for neoplastic gain FDA
approval . Mutation of V617F in JAK2 results in constitutive activation
downstream of erythropoietin (EPO), GM-CSF and thrombopoietin (TPO)
receptors. And it is associated strongly with myeloproliferative
neoplasms including myelofibrosis, polycythaemia vera (PCV) and
essential thrombocythaemia(Lundberg et al., 2014). On the one hand, as
to JAK-STAT pathway is constitutively activated in many kind of cancer,
recently JAKnibs are approved in many clinical trials treating
haematological and solid tumours(Johnson, O’Keefe & Grandis, 2018). On
the other hand, in the recent years, JAKnib find its usage in treating
inflammatory and immune disease, such as rheumatoid arthritis,
inflammatory bowel disease(IBD) and psoriasis. Futher more, as to
cardiovascular disease (CVD) is increasingly being seen as an
inflammatory process, JAKnib is found potential in treating
atherosclerosis(Tang et al., 2020; Yang et al., 2020). There are also
preliminary data showed the potentian of tofatinib (pan-JAK inhibitor)
in treating diabetic nephropathy(Tuttle et al., 2018). Recently, JAK
inhibitors are also point out to be potential theraputic candidates of
treating asthma(Sada, Watanabe, Nakamoto, Inui & Takizawa, 2020; Yu,
Shi, Shu, Ding & Lou, 2021), COPD(Beaulieu, Attwe, Breau, Lipskaia &
Adnot, 2021), ARDS and COVID-19 cytokine release syndrome(Luo, Li,
Jiang, Chen, Wang & Ye, 2020).
It has passed nearly 20 years from the first generation pan-JAK
inhibitors approved in treating myelofibrosis or rheumatoid arthritis.
There are more selective JAK inhibitors designed to adjust different
medical demand and they overcome the side effects of suppressing so many
cytokines indiscriminately(Kim et al., 2020),(Zhu et
al., 2020).
FIGURE 4 Chemical structure and attributes of various JAK
inhibitors. The first-generation Janus kinase (JAK) inhibitors
ruxolitinib, tofacitinib and baricitinib block multiple JAKs. The newer
pan-JAKinib peficitinib has a
median inhibitory concentration (IC50) of 3.9, 5.0, 0.71 and 4.8 nmol/L
for JAK1, JAK2, JAK3 and tyrosine kinase 2 (TYK2) enzymatic activity,
respectively. A variety of next-generation JAK inhibitors are emerging.
Several block JAKs and other kinases (R333, cerdulatinib and
pacritinib), whereas many are selective for one JAK isoform. Filgotinib,
upadacitinib and solcitinib block JAK1; Decernotinib, PF-06651600,
tubulosine, JANEX-1 (WHI-P131) block JAK3; and BMS986165, NDI-021232,
NDI-031407, PF-06700841 and SAR-20347 all block TYK2. Chemical
structures are shown.