Ruxolitinib

JAK1 & JAK2 inhibition by Ruxolitinib

JAK1 and JAK2 inhibitor

Ruxolitinib (also known as INCB018424) is a potent, reversible, and selective Janus Kinase (JAK) 1 and JAK2 inhibitor [1, 2]. Ruxolitinib was developed as a potential therapeutic for a family of blood cancers termed myeloproliferative neoplasms (MPNs), which are characterized by the aberrant activation of the JAK-STAT pathway due to a mutation (V617F) in JAK2 [1,3].

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Mode of action:

Ruxolitinib competes with ATP for binding to the catalytic site in the kinase domain and thus inhibits not only the mutated JAK2 but wild-type JAK1-2 signaling pathways. Inhibition of the JAK-STAT signaling pathway by Ruxolitinib results in a dramatic decrease in levels of inflammatory cytokines, such as IL-6 and TNF-α. It is with this attenuation of the inflammatory response that the clinical efficiency of Ruxolitinib is attributed [2].
Ruxolitinib is approved for the treatment of the MPNs, myelofibrosis, and polycythemia vera [3].  Pre-clinical data suggest that Ruxolitinib shows potential in the treatment of inflammatory conditions such as acute graft versus host disease (GvHD) [4]. Additionally, synergy has been reported between Ruxolitinib and the chemotherapy drug, dexamethasone, in the treatment of acute lymphoblastic leukemia (ALL) in both in vitro and in vivo pre-clinical models [5].

Key features of Ruxolitinib:

• Specific and potent JAK1 and JAK2 inhibitor
• Inhibitory function validated in cellular assays
• Highly pure (≥97%) and absence of any bacterial contamination has been confirmed

Ruxolitinib provided by InvivoGen is for research use only.

References

1. Quintas-Cardama A. et al., 2010. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115, 3109-3117.
2. Ajayi S. et al., 2018. Ruxolitinib. Recent Results Cancer Res 212, 119-132.
3. Mascarenhas J. & Hoffman R., 2012. Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res 18, 3008-3014.
4. Zeiser R. et al., 2020. Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host Disease. N Engl J Med 382, 1800-1810.
5. Verbeke D. et al., 2019. Ruxolitinib Synergizes With Dexamethasone for the Treatment of T-cell Acute Lymphoblastic Leukemia. Hemasphere 3, e310.

Figures

Effect of Ruxolitinib on HEK-Blue™ IFN-α/β cell response to type I and type III IFNs: HEK‑Blue™ IFN-α/β cells were incubated with 3 U/ml hIFN-α2b (grey), 1 U/ml hIFN-β1 (purple) or 10 ng/ml hIL-29 (hIFN-λ1) (red) and increasing concentrations of Ruxolitinib. After 24h incubation, IFN-induced ISG activation was assessed by measuring SEAP levels in the supernatant using QUANTI‑Blue™. Percentages of maximal response (no inhibitor) for each cytokine are shown.

Specifications

Synonym: INCB018424

CAS number: 941678-49-5

Formula: C₁₇H₁₈N₆ 

Molecular weight: 306.37

Solubility: 10 mg/ml in DMSO

Quality control:

• Purity ≥97% (UHPLC)
• Inhibitory activity validated in cellular assays
• The absence of bacterial contamination (e.g. lipoproteins and endotoxins) is confirmed using HEK-Blue™ TLR2 and HEK-Blue™ TLR4 cells.

Contents

• 5 mg Ruxolitinib

Ruxolitinib is shipped at room temperature.

 Upon receipt, store at -20 °C.

Details

Janus kinases

Janus kinases (JAKs) are constitutively bound to cytokine receptors, such as Type I interferons (IFNs) and interleukin-6. Upon binding of the ligand to the receptor, JAKs phosphorylate downstream targets such as STAT3/5, Akt, and ERK. Ultimately, this induces the production of cytokines and chemokines, including IFN-stimulated genes (ISGs). JAK-STAT signaling is crucial for the regulation and homeostasis of hematopoiesis and immunity [2].
 

1. Quintas-Cardama A. et al., 2010. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115, 3109-3117.
2. Ajayi S. et al., 2018. Ruxolitinib. Recent Results Cancer Res 212, 119-132.
 

Chemical structure of Ruxolitinib