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Ruxolitinib (INCB018424)JAK inhibitor

Ruxolitinib (INCB018424)

Catalog No. A3012
Size Price Stock Qty
Evaluation Sample $28.00 In stock
5mg $65.00 In stock
25mg $130.00 In stock
100mg $280.00 In stock

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Sample solution is provided at 25 µL, 10mM.

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Chemical structure

Ruxolitinib (INCB018424)

Related Biological Data

INCB018424
106 BaF3 Aut (V658I), Aut (F958V) were treated for 30 min with 100 nM, 1 μM or 10 μM INCB018424 inhibitor or with DMSO as a control (-condition), lysed and subjected to Western blot analysis. Phosphorylation of JAK1 and STAT5 was detected using specific anti-pY1034/35 JAK1 and anti-pY694 STAT5. Membranes were re-probed with anti-JAK1, anti-STAT5 and anti-β-Actin antibodies as a control. Similar results were obtained in 3 independent experiments.

Biological Activity

Description INCB018424 is the first potent, selective inhibitor of JAK1/2 to enter the clinic with IC50 of 3.3 nM/2.8 nM, >130-fold selectivity for JAK1/2 versus JAK3.
Targets JAK1 JAK2        
IC50 3.3 nM 2.8 nM        

Protocol

Cell experiment: [1]

Cell lines

Primary mononuclear cells isolated from patients with PV or normal control persons

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reacting condition

IC50: erythroid progenitors: 407 nM for normal donors, 223 nM for PV donors myeloid progenitors: 511 nM for normal donors, 444 nM for PV donors 14 days

Applications

Growth of clonogenic progenitors of erythroid (BFU-E) and myeloid origin (CFU-M) was assessed in colony-forming assays in the presence of increasing concentrations of INCB018424. Dose-dependent inhibition of the growth of erythroid and myeloid progenitors was observed with INCB018424. The mean IC50 for INCB018424 against erythroid progenitors was 407 nM for normal donors and 223 nM for PV donors. A similar effect was observed on myeloid progenitors (CFU-M), with IC50 values of 511 nM and 444 nM for control and PV samples, respectively.

Animal experiment: [2]

Animal models

C57BL/6N mice

Dosage form

Oral administration, 75 mg/kg

Application

Mice receiving 75 mg/kg ruxolitinib or vehicle 6 hours prior to and 6 hours after injection of OVA/CpG were analyzed for expression of activation markers on CD11c 1CD81 splenic DCs. Lower expression levels of CD40, CD80, CD86 as well as MHC I and II molecules were detected in ruxolitinib-challenged animals. Next, ruxolitinib or vehicle was fed to mice 6 hours prior to as well as 6 hours and 18 hours after priming with OVA/CpG and adoptive transfer of CFSE-labeled OT-I cells. Analysis of transferred CFSE-labeled OT-I T cells revealed reduced proliferation, CD25 expression, and IFN-production in mice pretreated with ruxolitinib.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood, 2010, 115(15): 3109-3117.

[2] Heine A, Held S A E, Daecke S N, et al. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood, 2013, 122(7): 1192-1202.

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Chemical Properties

Cas No. 941678-49-5 SDF Download SDF
Synonyms Ruxolitinib,INCB018424,INCB-018424
Chemical Name (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
Canonical SMILES C1CCC(C1)C(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3
Formula C17H18N6 M.Wt 306.37
Solubility Soluble in DMSO > 10 mM Storage Store at -20°C
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
Shipping Condition Evaluation sample solution : ship with blue ice
All other available size: ship with RT , or blue ice upon request

Research Update

1. The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers. J Clin Pharmacol. 2012 Jun;52(6):809-18. doi: 10.1177/0091270011405663. Epub 2011 May 20.
Abstract
Ruxolitinib is a JAK1/2 inhibitor that is primarily metablized by CYP3A4. A 50% reduce in ruxolitinib dosage is suggested for the combination therapy of ruxolitinib with a potent CYP3A4 inhibitor due to greatly increased PD activity of ruxolitinib; while no ruxolitinib dosage adjustment is suggested for the combination of reuxolitinib with inducers or mild/moderate inhibitors of CYP3A4 due to no significant change in PD activity.
2. Population pharmacokinetic analysis of orally-administered ruxolitinib (INCB018424 Phosphate) in patients with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia myelofibrosis (PET MF). J Clin Pharmacol. 2013 Jul;53(7):721-30. doi: 10.1002/jcph.102. Epub 2013 May 16.
Abstract
The PK of ruxolitinib, a JAK1/2 inhibitor approved for the treatment of myelofibrosis, was not significantly affected by gender and body weight indicating no need to adjust ruxolitinib dose based on these two factors.
3. Tumoricidal effects of the JAK inhibitor Ruxolitinib (INC424) on hepatocellular carcinoma in vitro. Cancer Lett. 2013 Dec 1;341(2):224-30. doi: 10.1016/j.canlet.2013.08.009. Epub 2013 Aug 11.
Abstract
Ruxolitinib is a JAK inhibitor that has been approved by FDA to treat advanced myelofibrosis. Since it’s a highly selective inhibitor of JAK/STAT signaling pathway, ruxolitinib significantly reduced proliferation, colony formation and expression of pSTAT1 and pSTAT3 in HCC cells.
4. Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. Blood. 2013 Dec 12;122(25):4047-53. doi: 10.1182/blood-2013-02-485888. Epub 2013 Oct 30.
Abstract
Ruxolitinib, a JAK1/2 inhibitor, was well tolerated in MF patients participating in a randomized trial, where ruxolitinib sustainably reduced splenomegaly in patients and prolonged overall survival of patients with manageable side effects, including anemia and thrombocytopenia.
5. Health-related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy. Br J Haematol. 2013 Jul;162(2):229-39. doi: 10.1111/bjh.12375. Epub 2013 May 14.
Abstract
In the phase 3 COMFORT-II study, ruxolitinib, a JAK1/2 inhibitor, exhibited better efficacy for the treatment of MF patients than BAT in terms of HRQoL improvement, symptom relief and a few other factors.

Background

Ruxolitinib dihydrochloride is a specific inhibitor of Janus-associated kinase (JAK1 and JAK2). Ruxolitinib is a small molecular with the formula of C17H21N6O4Pand Molecular Weight of 404. Ruxolitinib phosphate is an administered ATP-competitive cyclopentylpropionitrile derivative and shows inhibition activity on JAK1 and JAK2. Ruxolitinib inhibits phosphorylation of JAK1/2, STAT5, and ERK1/2, resulting in reduced cellular proliferation.

References

1. Ruxolitinib inhibits transforming JAK2 fusion proteins in vitro and induces complete cytogenetic remission in t (8; 9)(p22; p24)/PCM1-JAK2–positive chronic. E Lierman, D Selleslag, S Smits, J Billiet. Blood. 2012

2. Ruxolitinib for the treatment of myelofibrosis. A Ostojic, R Vrhovac, S Verstovsek.  Ther Clin Risk Manag. 2011