Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

Abstract

The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib

“…In addition, the clinical indication for JAK inhibitors has increased, and tofacitinib is also approved for the treatment of psoriatic arthritis and ulcerative colitis. 13 JAK inhibitors have shown great potential for the treatment of many rheumatic diseases, including systemic lupus erythematosus, dermatomyositis, systemic sclerosis, Sjögren syndrome, plaque psoriasis, vasculitis, inflammatory bowel disease, and even coronavirus disease 2019, by suppressing the signaling pathways of multiple cytokines and eventually controlling the inflammation. 7,14 Therefore, it is crucial to understand the potential adverse effects of these JAK inhibitors, such as tofacitinib, in HBV reactivation.…”

A Signaling View into the Inflammatory Tumor Microenvironment

“…The Janus kinase (JAK) family of nonreceptor tyrosine kinases includes JAK1, JAK2, JAK3, and TYK2. JAK family proteins associate with the intracellular domain of cytokine receptors, transducing cytokine-induced signals to the signal transducer and activator of transcription (STAT) family of transcription factors [179]. The JAK/STAT pathway contributes to the regulation of many cellular processes, including immunity, cell growth, cell death, and differentiation.…”

“…The JAK/STAT pathway contributes to the regulation of many cellular processes, including immunity, cell growth, cell death, and differentiation. Dysregulation of JAK/STAT signaling underlies several pathogenic conditions related to chronic inflammation, autoimmune diseases, and can-cer [179]. Among the seven mammalian STAT family members, STAT3 has been reported as having a vital role in modulating both endogenous and exogenous inflammatory signaling in tumors, by mediating the expression of inflammatory molecules triggered by oncogenic stimuli [180].…”

Advances on Greener Asymmetric Synthesis of Antiviral Drugs via Organocatalysis

“…Ruxolitinib (45) was the first drug used in the treatment of myelofibrosis and polycythemia vera (PCV), approved by the FDA in 2011. Ruxolitinib acts specifically in the inhibition of protein tyrosine janus kinases (JAK) 1 and 2, promoting a decrease in inflammation and an inhibition of cellular proliferation [74].…”