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Ruxolitinib (INCB018424)

Catalog No.: GC14191

Ruxolitinib (INCB018424) (INCB18424) is a potent and selective JAK1/2 inhibitor with IC50s of 3.3 nM and 2.8 nM in cell-free assays, and has 130-fold selectivity for JAK1/2 over JAK3. Ruxolitinib (INCB018424) induces autophagy and kills tumor cells through toxic mitophagy.

Ruxolitinib (INCB018424) Chemical Structure

Size Price Stock Qty
10mM (in 1mL DMSO)
$48.00
In stock
5mg
$49.00
In stock
25mg
$115.00
In stock
100mg
$199.00
In stock

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Sample solution is provided at 25 µL, 10mM.

Product Documents

Quality Control & SDS

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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.

Reaction Conditions

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

Applications

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.

Background

Ruxolitinib (INCB18424) is a potent and selective JAK1/2 inhibitor with IC50s of 3.3 nM and 2.8 nM in cell-free assays, and has 130-fold selectivity for JAK1/2 over JAK3.

Ruxolitinib potently and selectively inhibits JAK2V617F-mediated signaling and proliferation, markedly increases apoptosis in a dose dependent manner, and at 64 nM results in a doubling of cells with depolarized mitochondria in Ba/F3 cells. Ruxolitinib demonstrates remarkable potency against erythroid colony formation with IC50 of 67 nM, and inhibits proliferating of erythroid progenitors from normal donors and polycythemia vera patients with IC50 values of 407 nM and 223 nM, respectively[1].

Ruxolitinib (180 mg/kg, orally, twice a day) results in survive rate of greater than 90% by day 22 and markedly reduces splenomegaly and circulating levels of inflammatory cytokines, and preferentially eliminated neoplastic cells, resulting in significantly prolonged survival without myelosuppressive or immunosuppressive effects in a JAK2V617F-driven mouse model[1]. In the Ruxolitinib group, the primary end point is reached in 41.9% of patients, as compared with 0.7% in the placebo group in the double-blind trial of myelofibrosis. Ruxolitinib results in maintaining of reduction in spleen volume and improvement of 50% or more in the total symptom score[2]. Ruxolitinib (15 mg twice daily) treatment leads a total of 28% of the patients to have at least a 35% reduction in spleen volume at week 48 in patients with myelofibrosis, as compared with 0% in the group receiving the best available therapy. The mean palpable spleen length has decreased by 56% with Ruxolitinib but has increased by 4% with the best available therapy at week 48. Patients in the ruxolitinib group has an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis[3].

References:
[1]. Quintas-Cardama A, 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]. Verstovsek S, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med, 2012, 366(9), 799-807.
[3]. Harrison C, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012 Mar 1;366(9):787-98.

Chemical Properties

Cas No. 941678-49-5 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 ≥ 15.32mg/mL in DMSO 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

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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.

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