Ruxolitinib - JAK1 and JAK2 Inhibitor

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].

More details on Janus Kinase (JAK)

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:

• Specific and potent JAK1 and JAK2 inhibitor
• InvitroFit™ grade: highly pure (≥97%) and inhibitory function validated in cellular assays

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.