Uses
A JAK family kinase inhibitor of JAK1, JAK2 and JAK3 with IC50s of 2.7 nM, 4.5 nM and 322 nM, respectively
Uses
INCB018424 is the first potent, selective, JAK1/2 inhibitor to enter the clinic with IC50 of 3.3 nM/2.8 nM, >130-fold selectivity for JAK1/2 versus JAK3. Phase 3
Uses
Ruxolitinib is a selective Janus tyrosine kinase (JAK1 and JAK2) inhibitor used in the treatment of myeloproliferative neoplasms and psoriasis.
Definition
ChEBI: A pyrazole substituted at position 1 by a 2-cyano-1-cyclopentylethyl group and at position 3 by a pyrrolo[2,3-d]pyrimidin-4-yl group. Used as the phosphate salt for the treatment of patients with intermediate or high-risk myelofibrosis, includ
ng primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.
Uses
Janus-associated kinases (JAKs) are cytoplasmic tyrosine kinases that are required for activating the signaling of certain cytokines and growth factor receptors. A JAK2 gene fusion mutation, JAK2V617F, that causes unchecked activation of various growth factors and cytokines, has been linked to myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Ruxolitinib is a potent ATP mimetic that inhibits both JAK1 and JAK2 with IC50 values of 2.7 and 4.5 nM, respectively and is relatively less selective for JAK3 (IC50 = 322 nM). It can block interleukin-6 (IL-6) signaling (IC50 = 281 nM) and proliferation of JAK2V617F+ Ba/F3 cells (IC50 = 127 nM). In primary cultures, ruxolitinib preferentially suppresses erythroid progenitor colony formation from JAK2V617F+ polycythemia vera patients (IC50 = 67 nM) versus healthy donors (IC50 > 400 nM). In a mouse model of JAK2V617F+ MPN, 90 mg/kg ruxolitinib reduced splenomegaly, decreased circulating levels of IL-6 and TNF-α, eliminated neoplastic cells, and prolonged survival of the treated animals.[Cayman Chemical]
Description
In November 2011, the U.S. FDA approved ruxolitinib (INCB018424)
for the treatment of patients with intermediate or high-risk myelofibrosis.
Ruxolitinib is
an ATP-competitive inhibitor of JAK1 and JAK2 (IC50's of 3.3±1.2 nM
and 2.8±1.2 nM, respectively) and inhibition occurs regardless of the
JAK2V617F mutational status. Ruxolitinib is a moderately potent inhibitor
of the related JAK, TYK2 (IC50=19±3.2 nM) but is selective versus
JAK3 (IC50=428±243 nM). It was also selective versus a panel of 26 other
kinases at concentrations approximately 100-fold the IC50 of JAK1 and
JAK2. Inhibition of JAK1 and JAK2 downregulates the JAK-signal transducer
and activator of transcription (STAT) pathway, inhibiting
myeloproliferation, inducing apoptosis, and reducing numerous cytokine
plasma levels.
Originator
Incyte Corporation (United States)
Characteristics
Class: non-receptor tyrosine kinase
Treatment: MF, PV, cGVHD
Oral bioavailability >95%
Elimination half-life = 3 h
Protein binding = 97%
Clinical Use
Tyrosine kinase inhibitor:
Treatment of disease related splenomegaly or
symptoms in patients with primary myelofibrosis
(MF), post polycythaemia vera (PV) myelofibrosis
or post-essential thrombocythemia myelofibrosis
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: concentration increased by
clarithromycin and telithromycin, reduced dose of
ruxolitinib; concentration reduced by rifampicin.
Antifungals: reduce dose of ruxolitinib with
fluconazole, itraconazole, ketoconazole, posaconazole
and voriconazole.
Antipsychotics: avoid with clozapine, risk of
agranulocytosis.
Antivirals: reduce dose of ruxolitinib with
boceprevir, indinavir, lopinavir, ritonavir, saquinavir
and telaprevir.
Metabolism
Ruxolitinib is mainly metabolised by CYP3A4 (>50%),
with additional contribution from CYP2C9 to produce
2 major and active metabolites. About 74% of a dose is
excreted in the urine and about 22% via the faeces.
References
1) Verstovsek?et al. (2009),?Therapeutic potential of JAK2 inhibitors; Hematology Am. Soc. Hematol. Educ. Program,?2009(1)?636
2) Quintas-Cardama?et al. (2010),?Preclinical characterization of the selective JAK1/2 inhibitor INCB01824: Therapeutic implications for the treatment of myeloproliferative neoplasms; Blood,?115?3109
3) Farr et al. (2017) Targeting cellular senescence prevents age-related bone loss in mice; Nat. Med. 23 1072
4) Li?et al.?(2017)?Identification of a novel functional JAK1 S646P mutation in acute lymphoblastic leukemia; Oncotarget?8?34687
