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Identification
NameRuxolitinib
Accession NumberDB08877
TypeSmall Molecule
GroupsApproved
Description

Ruxolitinib is a janus-associated kinase inhibitor indicated to treat bone marrow cancer, specifically intermediate or high-risk myelofibrosis. FDA approved on November 16, 2011.

Structure
Thumb
Synonyms
INCB018424
INCB424
External Identifiers
  • INCB 18424
  • INCB018424
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Jakafitablet5 mg/1oralIncyte Corporation2011-11-16Not applicableUs
Jakafitablet25 mg/1oralIncyte Corporation2011-11-16Not applicableUs
Jakafitablet20 mg/1oralIncyte Corporation2011-11-16Not applicableUs
Jakafitablet15 mg/1oralIncyte Corporation2011-11-16Not applicableUs
Jakafitablet10 mg/1oralIncyte Corporation2011-11-16Not applicableUs
Jakavitablet15 mgoralNovartis Pharmaceuticals Canada Inc2012-07-19Not applicableCanada
Jakavitablet5 mgoralNovartis Pharmaceuticals Canada Inc2012-07-19Not applicableCanada
Jakavitablet10 mgoralNovartis Pharmaceuticals Canada Inc2015-04-15Not applicableCanada
Jakavitablet20 mgoralNovartis Pharmaceuticals Canada Inc2012-07-19Not applicableCanada
Approved Generic Prescription ProductsNot Available
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Ruxolitinib Phosphate
Thumb
  • InChI Key: JFMWPOCYMYGEDM-XFULWGLBSA-N
  • Monoisotopic Mass: 404.136189702
  • Average Mass: 404.3602
DBSALT000156
Categories
UNII82S8X8XX8H
CAS number941678-49-5
WeightAverage: 306.365
Monoisotopic: 306.159294606
Chemical FormulaC17H18N6
InChI KeyInChIKey=HFNKQEVNSGCOJV-OAHLLOKOSA-N
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
IUPAC Name
(3R)-3-cyclopentyl-3-(4-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}-1H-pyrazol-1-yl)propanenitrile
SMILES
N#CC[[email protected]](C1CCCC1)N1C=C(C=N1)C1=C2C=CNC2=NC=N1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as pyrrolopyrimidines. These are compounds containing a pyrrolopyrimidine moiety, which consists of a pyrrole ring fused to a pyrimidine. Pyrrole is 5-membered ring consisting of four carbon atoms and one nitrogen atom. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPyrrolopyrimidines
Sub ClassNot Available
Direct ParentPyrrolopyrimidines
Alternative Parents
Substituents
  • Pyrrolopyrimidine
  • Pyrimidine
  • Heteroaromatic compound
  • Pyrrole
  • Pyrazole
  • Azole
  • Azacycle
  • Nitrile
  • Carbonitrile
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Aromatic heteropolycyclic compound
Molecular FrameworkAromatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationTreatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera (post-PV) myelofibrosis and post-essential thrombocythemia (post-ET) myelofibrosis. [Lexicomp] Myeolofibrosis is the proliferation of abnormal bone marrow stem cells which cause fibrosis (the excessive formation of connective tissue).
PharmacodynamicsThe mean half-maximal inhibitory concentration (IC50) for JAK 1 and JAK 2 are 2.8 nmol/L and 3.3 nmol/L respectively. After administration of ruxolitinib, a decrease in levels of phosphorylated STAT (marker for JAK activity) in a dose-dependent manner can be observed. Pharmacodynamic resistance has not been observed.
Mechanism of actionRuxolitinib is a kinase inhibitor that is selective for the Janus Associated Kinases (JAK) 1 and 2. These kinases are responsible for the mediation of cytokine and growth factor signalling which in turn effect immune function and hematopoiesis. The signalling process involves signal transducers and transcription activators (STAT) which modulate gene expression. Patients with myelofibrosis have abnormal JAK1 and JAK2 activity thus ruxolitinib works to regulate this.
Related Articles
AbsorptionAbsorption is rapid and is not affected by food. Cmax, 15 mg, healthy subject = 649 nmol/L; Tmax, 15 mg, healthy subject = 1.5 hours; Ruxolitinib does not accumulate significantly.
Volume of distribution

Terminal phase volume of distribution, 15 mg, healthy subject = 76.6 L.

Protein binding97% protein bound, primarily to albumin.
Metabolism

Ruxolitinib is metabolized by CYP3A4. Less potent active metabolites forms as a result.

Route of eliminationEliminated via urine (74%, <1% as unchanged drug) and feces (22%, <1% as unchanged drug).
Half lifeMean elimination half-life, 15 mg, healthy subject = 2.8 hours.
Clearance

15 mg, healthy subject = 18.7 L/h.

ToxicityThrombocytopenia was the dose-limiting toxicity.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9673
Caco-2 permeable-0.5198
P-glycoprotein substrateNon-substrate0.7838
P-glycoprotein inhibitor INon-inhibitor0.8228
P-glycoprotein inhibitor IIInhibitor0.7092
Renal organic cation transporterNon-inhibitor0.5098
CYP450 2C9 substrateNon-substrate0.8394
CYP450 2D6 substrateNon-substrate0.8075
CYP450 3A4 substrateNon-substrate0.6535
CYP450 1A2 substrateInhibitor0.6426
CYP450 2C9 inhibitorNon-inhibitor0.7731
CYP450 2D6 inhibitorNon-inhibitor0.9208
CYP450 2C19 inhibitorNon-inhibitor0.6689
CYP450 3A4 inhibitorNon-inhibitor0.6655
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.5753
Ames testAMES toxic0.5681
CarcinogenicityNon-carcinogens0.9308
BiodegradationNot ready biodegradable0.9917
Rat acute toxicity2.5724 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.633
hERG inhibition (predictor II)Non-inhibitor0.8772
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
Tabletoral10 mg/1
Tabletoral15 mg/1
Tabletoral20 mg/1
Tabletoral25 mg/1
Tabletoral5 mg/1
Tabletoral10 mg
Tabletoral15 mg
Tabletoral20 mg
Tabletoral5 mg
PricesNot Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US7598257 No2007-12-242027-12-24Us
US8415362 No2007-12-242027-12-24Us
US8722693 No2008-06-122028-06-12Us
US8822481 No2008-06-122028-06-12Us
US8829013 No2008-06-122028-06-12Us
US9079912 No2006-12-122026-12-12Us
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubilitySoluble in aqueous buffers across a pH of 1-8FDA label.
Predicted Properties
PropertyValueSource
Water Solubility0.116 mg/mLALOGPS
logP2.94ALOGPS
logP2.48ChemAxon
logS-3.4ALOGPS
pKa (Strongest Acidic)13.89ChemAxon
pKa (Strongest Basic)5.51ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area83.18 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity98.01 m3·mol-1ChemAxon
Polarizability33.04 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis ReferenceNot Available
General References
  1. Cervantes F, Martinez-Trillos A: Myelofibrosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013 May;14(7):873-84. doi: 10.1517/14656566.2013.783019. Epub 2013 Mar 21. [PubMed:23514013 ]
  2. Yang LP, Keating GM: Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012 Nov 12;72(16):2117-27. doi: 10.2165/11209340-000000000-00000. [PubMed:23061804 ]
External Links
ATC CodesL01XE18
AHFS Codes
  • 10:00
PDB EntriesNot Available
FDA labelDownload (399 KB)
MSDSDownload (210 KB)
Interactions
Drug Interactions
Drug
AcebutololRuxolitinib may increase the bradycardic activities of Acebutolol.
AmiodaroneRuxolitinib may increase the bradycardic activities of Amiodarone.
AprepitantThe serum concentration of Ruxolitinib can be increased when it is combined with Aprepitant.
AtazanavirThe serum concentration of Ruxolitinib can be increased when it is combined with Atazanavir.
AtenololRuxolitinib may increase the bradycardic activities of Atenolol.
BeractantRuxolitinib may increase the bradycardic activities of Beractant.
BetaxololRuxolitinib may increase the bradycardic activities of Betaxolol.
BexaroteneThe serum concentration of Ruxolitinib can be decreased when it is combined with Bexarotene.
BisoprololRuxolitinib may increase the bradycardic activities of Bisoprolol.
BoceprevirThe serum concentration of Ruxolitinib can be increased when it is combined with Boceprevir.
BosentanThe serum concentration of Ruxolitinib can be decreased when it is combined with Bosentan.
CalfactantRuxolitinib may increase the bradycardic activities of Calfactant.
CarteololRuxolitinib may increase the bradycardic activities of Carteolol.
CarvedilolRuxolitinib may increase the bradycardic activities of Carvedilol.
CeritinibThe serum concentration of Ruxolitinib can be increased when it is combined with Ceritinib.
ClarithromycinThe serum concentration of Ruxolitinib can be increased when it is combined with Clarithromycin.
ClonidineRuxolitinib may increase the bradycardic activities of Clonidine.
ClozapineThe risk or severity of adverse effects can be increased when Ruxolitinib is combined with Clozapine.
CobicistatThe serum concentration of Ruxolitinib can be increased when it is combined with Cobicistat.
ConivaptanThe serum concentration of Ruxolitinib can be increased when it is combined with Conivaptan.
CrizotinibRuxolitinib may increase the bradycardic activities of Crizotinib.
DabrafenibThe serum concentration of Ruxolitinib can be decreased when it is combined with Dabrafenib.
DarunavirThe serum concentration of Ruxolitinib can be increased when it is combined with Darunavir.
DasatinibThe serum concentration of Ruxolitinib can be increased when it is combined with Dasatinib.
DeferasiroxThe serum concentration of Ruxolitinib can be decreased when it is combined with Deferasirox.
DenosumabThe risk or severity of adverse effects can be increased when Denosumab is combined with Ruxolitinib.
DexmedetomidineRuxolitinib may increase the bradycardic activities of Dexmedetomidine.
DigoxinRuxolitinib may increase the bradycardic activities of Digoxin.
DiltiazemRuxolitinib may increase the bradycardic activities of Diltiazem.
DonepezilRuxolitinib may increase the bradycardic activities of Donepezil.
DronedaroneRuxolitinib may increase the bradycardic activities of Dronedarone.
EsmololRuxolitinib may increase the bradycardic activities of Esmolol.
FingolimodRuxolitinib may increase the bradycardic activities of Fingolimod.
FluconazoleThe metabolism of Ruxolitinib can be decreased when combined with Fluconazole.
FosaprepitantThe serum concentration of Ruxolitinib can be increased when it is combined with Fosaprepitant.
Fusidic AcidThe serum concentration of Ruxolitinib can be increased when it is combined with Fusidic Acid.
GalantamineRuxolitinib may increase the bradycardic activities of Galantamine.
GuanfacineRuxolitinib may increase the bradycardic activities of Guanfacine.
IdelalisibThe serum concentration of Ruxolitinib can be increased when it is combined with Idelalisib.
IndinavirThe serum concentration of Ruxolitinib can be increased when it is combined with Indinavir.
ItraconazoleThe serum concentration of Ruxolitinib can be increased when it is combined with Itraconazole.
IvabradineRuxolitinib may increase the bradycardic activities of Ivabradine.
IvacaftorThe serum concentration of Ruxolitinib can be increased when it is combined with Ivacaftor.
KetoconazoleThe serum concentration of Ruxolitinib can be increased when it is combined with Ketoconazole.
LabetalolRuxolitinib may increase the bradycardic activities of Labetalol.
LanreotideRuxolitinib may increase the bradycardic activities of Lanreotide.
LeflunomideThe risk or severity of adverse effects can be increased when Ruxolitinib is combined with Leflunomide.
LevobunololRuxolitinib may increase the bradycardic activities of Levobunolol.
LucinactantRuxolitinib may increase the bradycardic activities of Lucinactant.
LuliconazoleThe serum concentration of Ruxolitinib can be increased when it is combined with Luliconazole.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Ruxolitinib.
MethyldopaRuxolitinib may increase the bradycardic activities of Methyldopa.
MetipranololRuxolitinib may increase the bradycardic activities of Metipranolol.
MetoprololRuxolitinib may increase the bradycardic activities of Metoprolol.
MifepristoneThe serum concentration of Ruxolitinib can be increased when it is combined with Mifepristone.
MitotaneThe serum concentration of Ruxolitinib can be decreased when it is combined with Mitotane.
NadololRuxolitinib may increase the bradycardic activities of Nadolol.
NatalizumabThe risk or severity of adverse effects can be increased when Ruxolitinib is combined with Natalizumab.
NebivololRuxolitinib may increase the bradycardic activities of Nebivolol.
NefazodoneThe serum concentration of Ruxolitinib can be increased when it is combined with Nefazodone.
NelfinavirThe serum concentration of Ruxolitinib can be increased when it is combined with Nelfinavir.
NetupitantThe serum concentration of Ruxolitinib can be increased when it is combined with Netupitant.
OctreotideRuxolitinib may increase the bradycardic activities of Octreotide.
PalbociclibThe serum concentration of Ruxolitinib can be increased when it is combined with Palbociclib.
PasireotideRuxolitinib may increase the bradycardic activities of Pasireotide.
PenbutololRuxolitinib may increase the bradycardic activities of Penbutolol.
PhenytoinThe metabolism of Ruxolitinib can be increased when combined with Phenytoin.
PimecrolimusThe risk or severity of adverse effects can be increased when Pimecrolimus is combined with Ruxolitinib.
PindololRuxolitinib may increase the bradycardic activities of Pindolol.
Poractant alfaRuxolitinib may increase the bradycardic activities of Poractant alfa.
PosaconazoleThe serum concentration of Ruxolitinib can be increased when it is combined with Posaconazole.
PropafenoneRuxolitinib may increase the bradycardic activities of Propafenone.
PropranololRuxolitinib may increase the bradycardic activities of Propranolol.
RitonavirThe serum concentration of Ruxolitinib can be increased when it is combined with Ritonavir.
RivastigmineRuxolitinib may increase the bradycardic activities of Rivastigmine.
RoflumilastRoflumilast may increase the immunosuppressive activities of Ruxolitinib.
SaquinavirThe serum concentration of Ruxolitinib can be increased when it is combined with Saquinavir.
SiltuximabThe serum concentration of Ruxolitinib can be decreased when it is combined with Siltuximab.
SimeprevirThe serum concentration of Ruxolitinib can be increased when it is combined with Simeprevir.
Sipuleucel-TThe therapeutic efficacy of Sipuleucel-T can be decreased when used in combination with Ruxolitinib.
SotalolRuxolitinib may increase the bradycardic activities of Sotalol.
St. John's WortThe serum concentration of Ruxolitinib can be decreased when it is combined with St. John&#39;s Wort.
StiripentolThe serum concentration of Ruxolitinib can be increased when it is combined with Stiripentol.
SufentanilRuxolitinib may increase the bradycardic activities of Sufentanil.
TacrolimusThe risk or severity of adverse effects can be increased when Tacrolimus is combined with Ruxolitinib.
TelaprevirThe serum concentration of Ruxolitinib can be increased when it is combined with Telaprevir.
TelithromycinThe serum concentration of Ruxolitinib can be increased when it is combined with Telithromycin.
TimololRuxolitinib may increase the bradycardic activities of Timolol.
TizanidineRuxolitinib may increase the bradycardic activities of Tizanidine.
TocilizumabThe serum concentration of Ruxolitinib can be decreased when it is combined with Tocilizumab.
TofacitinibRuxolitinib may increase the immunosuppressive activities of Tofacitinib.
TrastuzumabTrastuzumab may increase the neutropenic activities of Ruxolitinib.
VerapamilRuxolitinib may increase the bradycardic activities of Verapamil.
VoriconazoleThe serum concentration of Ruxolitinib can be increased when it is combined with Voriconazole.
Food Interactions
  • Take without regards to meals

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Ubiquitin protein ligase binding
Specific Function:
Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
Gene Name:
JAK1
Uniprot ID:
P23458
Molecular Weight:
133275.995 Da
References
  1. Cervantes F, Martinez-Trillos A: Myelofibrosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013 May;14(7):873-84. doi: 10.1517/14656566.2013.783019. Epub 2013 Mar 21. [PubMed:23514013 ]
  2. Yang LP, Keating GM: Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012 Nov 12;72(16):2117-27. doi: 10.2165/11209340-000000000-00000. [PubMed:23061804 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Sh2 domain binding
Specific Function:
Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR)...
Gene Name:
JAK2
Uniprot ID:
O60674
Molecular Weight:
130672.475 Da
References
  1. Cervantes F, Martinez-Trillos A: Myelofibrosis: an update on current pharmacotherapy and future directions. Expert Opin Pharmacother. 2013 May;14(7):873-84. doi: 10.1517/14656566.2013.783019. Epub 2013 Mar 21. [PubMed:23514013 ]
  2. Yang LP, Keating GM: Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012 Nov 12;72(16):2117-27. doi: 10.2165/11209340-000000000-00000. [PubMed:23061804 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. Yang LP, Keating GM: Ruxolitinib: in the treatment of myelofibrosis. Drugs. 2012 Nov 12;72(16):2117-27. doi: 10.2165/11209340-000000000-00000. [PubMed:23061804 ]
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Drug created on May 13, 2013 12:21 / Updated on August 24, 2016 01:53