A Comprehensive Overview of Globally Approved JAK Inhibitors

Abstract

Janus kinase (JAK) is a family of cytoplasmic non-receptor tyrosine kinases that includes four members, namely JAK1, JAK2, JAK3, and TYK2. The JAKs transduce cytokine signaling through the JAK-STAT pathway, which regulates the transcription of several genes involved in inflammatory, immune, and cancer conditions. Targeting the JAK family kinases with small-molecule inhibitors has proved to be effective in the treatment of different types of diseases. In the current review, eleven of the JAK inhibitors that received approval for clinical use have been discussed. These drugs are abrocitinib, baricitinib, delgocitinib, fedratinib, filgotinib, oclacitinib, pacritinib, peficitinib, ruxolitinib, tofacitinib, and upadacitinib. The aim of the current review was to provide an integrated overview of the chemical and pharmacological data of the globally approved JAK inhibitors. The synthetic routes of the eleven drugs were described. In addition, their inhibitory activities against different kinases and their pharmacological uses have also been explained. Moreover, their crystal structures with different kinases were summarized, with a primary focus on their binding modes and interactions. The proposed metabolic pathways and metabolites of these drugs were also illustrated. To sum up, the data in the current review could help in the design of new JAK inhibitors with potential therapeutic benefits in inflammatory and autoimmune diseases.

SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition

“…Type II interferon binds to IFNγR2 resulting in oligomerization and transphosphorylation with IFNγR1 which then activates JAK1/JAK2 [ 24 ]. JAK inhibitor selectivity measured with in vitro kinase assays have demonstrated upadacitinib to be more selective for JAK1 and TYK2, baricitinib and ruxolitinib more selective for JAK1 and JAK2, and tofacitinib more selective for JAK1 and JAK3 [ 25 , 26 ]. Studies comparing the in vitro cellular pharmacology of leukocyte sub-populations at clinically relevant levels have demonstrated some differences between these JAK inhibitors based on distinct cytokine pathways with the most potent inhibitor of IFN-γ being tofacitinib and the most potent inhibitors of IFN-α being upadacitinib and tofacitinib [ 26 ].…”

STAT3 Inhibitors: A Novel Insight for Anticancer Therapy of Pancreatic Cancer

“…At present, four key JAK molecules have been identified, namely JAK1, JAK2, JAK3, and TK2 [ 21 ]. Among them, JAK3 is only expressed in cells of the hematopoietic and lymphoid systems, while the remaining three are expressed in almost all cells [ 11 , 22 , 23 ].…”

Update on dermatomyositis

“…IFN1 exposure decreased muscle stem cells’ (MuSC) proliferation; impaired myoblasts differentiation and fusion; induced myotubes atrophy and IFN-α production; and impaired endothelial cells angiogenesis [60,63,64 ▪▪ ]. Blocking IFN1-signaling cascade via Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway activation by antiinterferon alpha-beta receptor, anti-IFN-α, anti-IFN-β, and ruxolitinib (preferentially JAK1 and JAK2 inhibitors), prevented and reversed these effects in muscle and endothelial cells [64 ▪▪ ,65 ▪ ,66,67]. Interestingly, normal MuSC showed proliferation defect after exposure to dermatomyositis MuSC culture medium supernatant; adding ruxolitinib into the medium prevented the proliferation defect [64 ▪▪ ].…”

“…IFN1 signaling pathway-targeting therapy by the first-generation JAK inhibitors (off-label studies): ruxolitinib, tofacitinib, and baricitinib, showed promising results in dermatomyositis [69]. Notably, ruxolitinib mainly inhibits JAK1 and JAK2 and has moderate activity against tyrosine kinase 2 (TYK2); tofacitinib mainly inhibits JAK1 and JAK3 with less activity against JAK2 and TYK2; and baricitinib has high activity against JAK1 and JAK2, moderate activity against TYK2, and less activity against JAK3 [66,70,71 ▪▪ ]. In juvenile [72–78] and adult [60,79–100] patients with refractory dermatomyositis, ruxolitinib, tofacitinib, and baricitinib improved skin lesions [60,72–85,87–90,94,97,100], muscle strength [60,72–80,85,94,97], joint symptoms [72,76,77,82,92,94,96], ILD [75–77,81,83,86,88,90,91,93,95], and induced hair regrowth in patients with concurrent alopecia [80,82,99].…”