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Ruxolitinib (INCB018424)

JAK inhibitor CAS# 941678-49-5

Ruxolitinib (INCB018424)

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Quality Control of Ruxolitinib (INCB018424)

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Chemical structure

Ruxolitinib (INCB018424)

3D structure

Chemical Properties of Ruxolitinib (INCB018424)

Cas No. 941678-49-5 SDF Download SDF
PubChem ID 25126798 Appearance Powder
Formula C17H18N6 M.Wt 306.37
Type of Compound N/A Storage Desiccate at -20°C
Synonyms INCB018424
Solubility Soluble in DMSO > 10 mM
Chemical Name (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propanenitrile
SMILES C1CCC(C1)C(CC#N)N2C=C(C=N2)C3=C4C=CNC4=NC=N3
Standard InChIKey HFNKQEVNSGCOJV-OAHLLOKOSA-N
Standard InChI InChI=1S/C17H18N6/c18-7-5-15(12-3-1-2-4-12)23-10-13(9-22-23)16-14-6-8-19-17(14)21-11-20-16/h6,8-12,15H,1-5H2,(H,19,20,21)/t15-/m1/s1
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.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Ruxolitinib (INCB018424)

DescriptionINCB018424 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.
TargetsJAK1JAK2    
IC503.3 nM2.8 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.

Ruxolitinib (INCB018424) Dilution Calculator

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Preparing Stock Solutions of Ruxolitinib (INCB018424)

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.264 mL 16.3201 mL 32.6403 mL 65.2805 mL 81.6007 mL
5 mM 0.6528 mL 3.264 mL 6.5281 mL 13.0561 mL 16.3201 mL
10 mM 0.3264 mL 1.632 mL 3.264 mL 6.5281 mL 8.1601 mL
50 mM 0.0653 mL 0.3264 mL 0.6528 mL 1.3056 mL 1.632 mL
100 mM 0.0326 mL 0.1632 mL 0.3264 mL 0.6528 mL 0.816 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

Research Update of Ruxolitinib (INCB018424)

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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Background on Ruxolitinib (INCB018424)

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

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References on Ruxolitinib (INCB018424)

The effect of CYP3A4 inhibition or induction on the pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in healthy volunteers.[Pubmed:21602517]

J Clin Pharmacol. 2012 Jun;52(6):809-18.

Ruxolitinib, a selective Janus kinase (JAK) 1&2 inhibitor in development for the treatment of myeloproliferative neoplasms, is primarily metabolized by CYP3A4. The effects of inhibition or induction of CYP3A4 on single oral dose ruxolitinib pharmacokinetics (PK) and pharmacodynamics (PD) were evaluated in healthy volunteers. Coadministration of ketoconazole (a potent CYP3A4 inhibitor) and erythromycin (a moderate CYP3A4 inhibitor) increased total ruxolitinib plasma exposure (AUC(0-infinity)) by 91% and 27%, respectively, and ruxolitinib PD, as measured by the inhibition of interleukin (IL)-6-stimulated STAT3 phosphorylation in whole blood, was generally consistent with the PK observed. Pretreatment with rifampin, a potent CYP3A4 inducer, decreased ruxolitinib AUC(0-infinity) by 71% while resulting in only a 10% decrease in the overall PD activity. This apparent PK/PD discrepancy may be explained, in part, by an increase in the relative abundance of ruxolitinib active metabolites with the rifampin coadministration. The collective PK/PD data suggest that starting doses of ruxolitinib should be reduced by 50% if coadministered with a potent CYP3A4 inhibitor, whereas adjustments in ruxolitinib starting doses may not be needed when coadministered with inducers or mild/moderate inhibitors of CYP3A4. All study doses of ruxolitinib were generally safe and well tolerated when given alone and in combination with ketoconazole, erythromycin, or rifampin.

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).[Pubmed:23677817]

J Clin Pharmacol. 2013 Jul;53(7):721-30.

Ruxolitinib is a selective inhibitor of Janus kinase 1 and 2, which is approved to treat intermediate or high-risk myelofibrosis. The population pharmacokinetics for ruxolitinib were characterized by a modeling dataset of 272 subjects from a Phase 2 and a Phase 3 study and validated by an external validation dataset of 142 subjects from a second Phase 3 study. The PK of ruxolitinib was adequately described by a two-compartment disposition model with first-order absorption and linear elimination. All model parameters were estimated with good precision. Gender and body weight were identified as covariates for oral clearance (CL/F) and volume of distribution for central compartment (Vc/F), respectively. Apparent oral clearance was 22.1 and 17.7 L/h for a typical male and female subject, respectively, with 39.1% unexplained inter-individual variability (IIV). The typical Vc /F for a subject with a median weight of 72.9 kg was estimated to be 58.6 L, with 28% unexplained IIV. The model predictive performance was validated by visual predictive check (VPC) and the external validation dataset. This analysis suggests that effects of gender and body weight on ruxolitinib PK are not clinically significant and hence no dose adjustment is needed based on gender and weight.

Pharmacokinetics and pharmacodynamics of orally administered ruxolitinib (INCB018424 phosphate) in renal and hepatic impairment patients.[Pubmed:27128228]

Clin Pharmacol Drug Dev. 2014 Jan;3(1):34-42.

Hepatic and renal impairment studies were conducted with ruxolitinib, a JAK1&2 inhibitor that is cleared predominantly by metabolism. Both studies were open label, single-dose studies. Ruxolitinib area under the curve (AUC) was increased by 87%, 28%, and 65%, respectively, in subjects with mild, moderate, and severe hepatic impairment compared to healthy subjects with no correlation between exposure of ruxolitinib and the degree of hepatic impairment. The pharmacodynamics (PD) data were consistent with ruxolitinib pharmacokinetics (PK). The renal impairment study showed a surprising finding. While there was no change in ruxolitinib PK with varying degrees of renal impairment, the PD showed increasing pharmacological activity with increased severity of renal impairment. Analysis of the metabolite exposures revealed that active metabolites contributed to the observed incremental increase in PD activity. The recovery of ruxolitinib in dialysate was negligible. The starting dose of ruxolitinib in subjects with any hepatic impairment or moderate or severe renal impairment should be decreased to 10 mg twice daily (BID) if their platelet counts are between 100 x 10(9) /L and 150 x 10(9) /L. Subjects on dialysis should initiate dosing with a single dose of 15 or 20 mg, based on platelet counts, with dosing only on the days of dialysis.

Description

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 induces autophagy and kills tumor cells through toxic mitophagy.

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