NAV

Ruxolitinib

Identification

Summary

Ruxolitinib is a kinase inhibitor used to treat various types of myelofibrosis, polycythemia vera in patients who have not responded to or cannot tolerate hydroxyurea, and to treat graft-versus-host disease in cases that are refractory to steroid treatment.

Brand Names
Jakafi, Jakavi, Opzelura
Generic Name
Ruxolitinib
DrugBank Accession Number
DB08877
Background

Ruxolitinib, formerly known as INCB018424 or INC424, is an anticancer drug and a Janus kinase (JAK) inhibitor. It is a potent and selective inhibitor of JAK1 and JAK2,3 which are tyrosine kinases involved in cytokine signalling and hematopoiesis.2 Myeloproliferative neoplasms, such as myelofibrosis and polycythemia vera, are often characterized by aberrant activation of the JAK-STAT pathway, leading to abnormal blood cell counts and thrombotic complications. By inhibiting JAK1 and JAK2, ruxolitinib works to block the dysregulated cell signalling pathways and prevents abnormal blood cell proliferation.5 Due to a large number of patients with myeloproliferative neoplasms who have JAK2 mutations, ruxolitinib was the first ATP-competitive inhibitor of JAK1 and JAK2 ever developed.15

Ruxolitinib was first approved for the treatment of adult patients with myelofibrosis by the FDA in 2011, followed by EMA's approval in 2012.5 In 2014, it was approved for the treatment of polycythemia vera in adults who have an inadequate response to or are intolerant of hydroxyurea and in 2019, ruxolitinib was approved for use in steroid-refractory acute graft-versus-host disease in adults and children.19 The topical formulation of ruxolitinib is used to treat atopic dermatitis and vitiligo.23 It is being investigated for other inflammatory skin conditions.12

Ruxolitinib has been investigated to treat patients with coronavirus disease 2019 (COVID-19) accompanied by severe systemic hyperinflammation. In phase II clinical trials, ruxolitinib improved chest computed tomography and improved recovery in patients with lymphopenia.6,7 However, phase III clinical trials later determined that ruxolitinib was inadequate in meeting its primary endpoint of reducing the number of hospitalized COVID-19 patients who experienced severe complications 20 thus the drug was not approved as a treatment for COVID-19.

Type
Small Molecule
Groups
Approved
Structure
3D
Similar Structures
Weight
Average: 306.365
Monoisotopic: 306.159294606
Chemical Formula
C17H18N6
Synonyms
  • Ruxolitinib
External IDs
  • INC-424
  • INC424
  • INCB 18424
  • INCB-018424
  • INCB-18424
  • INCB018424
  • INCB18424
  • INCB424

Pharmacology

Indication

Ruxolitinib is indicated for the treatment of the following conditions:

  • intermediate or high-risk myelofibrosis (MF), including prima1y MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults.16 It is also used to treat disease-related splenomegaly or symptoms in adult patients with these conditions.22
  • polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea.16
  • steroid-refracto1y acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.16
  • chronic GVHD in patients aged 12 years and older who have failed one or two lines of systemic therapy.16

Topical ruxolitinib is indicated for:

  • the short-term and non-continuous chronic treatment of mild to moderate atopic dermatitis in non-immunocompromised patients patients 12 years of age and older whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.23
  • the treatment of nonsegmental vitiligo in adult and pediatric patients 12 years of age and older.23
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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Ruxolitinib is an antineoplastic agent that inhibits cell proliferation, induces apoptosis of malignant cells, and reduces pro-inflammatory cytokine plasma levels by inhibiting JAK-induced phosphorylation of signal transducer and activator of transcription (STAT).4 Inhibition of STAT3 phosphorylation, which is used as a marker of JAK activity, 2 by ruxolitinib is achieved at two hours after dosing which returned to near baseline by 10 hours in patients with myelofibrosis and polycythemia vera.16 In clinical trials, ruxolitinib reduced splenomegaly and improved symptoms of myelofibrosis.4 In a mouse model of myeloproliferative neoplasms, administration of ruxolitinib was associated with prolonged survival.2 Ruxolitinib inhibits both mutant and wild-type JAK2 4; however, JAK2V617F mutation, which is often seen in approximately 50% of patients with myelofibrosis, was shown to reduce ruxolitinib sensitivity, which may also be associated with possible resistance to JAK inhibitor treatment.14

Mechanism of action

The Janus kinase (JAK) family of protein tyrosine kinases comprises JAK1, JAK2, JAK3, and non-receptor tyrosine kinase 2 (TYK2).4 JAKs play a pivotal role in intracellular signalling pathways of various cytokines and growth factors essential to hematopoiesis, such as interleukin, erythropoietin, and thrombopoietin.2 JAKs have diverse functions: JAK1 and JAK3 promote lymphocyte differentiation, survival, and function, while JAK2 promotes signal transduction of erythropoietin and thrombopoietin.4,10 JAKs are in close proximity to the cytokine and growth factor receptor’s cytoplasmic region. Upon binding of cytokines and growth factors, JAKs are activated, undergoing cross-phosphorylation and tyrosine phosphorylation. This process also reveals selective binding sites for STATs, which are DNA-binding proteins that also bind to the cytoplasmic region of cytokine or growth factor receptors. Activated JAKs and STATs translocate to the nucleus as transcription factors to regulate gene expression of pro-inflammatory cytokines such as IL-6, IL-10, and nuclear factor κB (NF-κB).15 They also activate downstream pathways that promote erythroid, myeloid, and megakaryocytic development.4

The molecular pathogenesis of myeloproliferative neoplasms is not fully understood; however, JAK2 is constitutively activated and the JAK-STAT signalling pathway becomes deregulated and aberrant.2,15 Ruxolitinib is a selective and potent inhibitor of JAK2 and JAK1, with some affinity against JAK3 and TYK2. Anticancer effects of ruxolitinib are attributed to its inhibition of JAKs and JAK-mediated phosphorylation of STAT3.16 By downregulating the JAK-STAT pathway, ruxolitinib inhibits myeloproliferation and suppresses the plasma levels of pro-inflammatory cytokines such as IL-6 and TNF-α.4

Activated JAKs are also implicated in graft-versus-host-disease (GVHD), which is a severe immune complication of allogeneic hematopoietic cell transplantation GVHD is associated with significant morbidity and mortality, especially for patients who do not respond well to corticosteroid therapy. Activated JAKS stimulate T-effector cell responses, leading to increased proliferation of effector T cells and heightened production of pro-inflammatory cytokines. By blocking JAK1 and JAk2, ruxolitinib inhibits donor T-cell expansion and suppresses pro-inflammatory responses.13

TargetActionsOrganism
ATyrosine-protein kinase JAK2
inhibitor
Humans
ATyrosine-protein kinase JAK1
inhibitor
Humans
ATyrosine-protein kinase JAK3
inhibitor
Humans
ANon-receptor tyrosine-protein kinase TYK2
inhibitor
Humans
Absorption

Following oral administration, ruxolitinib undergoes rapid absorption 10 and the peak concentrations are reached within one hour after administration.4 Over a single-dose range of 5 mg to 200 mg, the mean maximal plasma concentration (Cmax) increases proportionally. Cmax ranged from 205 nM to 7100 nM and AUC ranged from 862 nM x hr to 30700 nM x hr. Tmax ranges from one to two hours following oral administration. Oral bioavailability is at least 95%.16

Volume of distribution

The mean volume of distribution (%coefficient of variation) at steady-state is 72 L (29%) in patients with myelofibrosis and 75 L (23%) in patients with polycythemia vera.16 It is not known whether ruxolitinib crosses the blood-brain barrier.21

Protein binding

Ruxolitinib is approximately 97% bound to plasma proteins, mostly to albumin.16

Metabolism

More than 99% of orally-administered ruxolitinib undergoes metabolism4 mediated by CYP3A4 and, to a lesser extent, CYP2C9.16 The major circulating metabolites in human plasma were M18 formed by 2-hydroxylation, and M16 and M27 (stereoisomers) formed by 3-hydroxylation. Other identified metabolites include M9 and M49, which are formed by hydroxylation and ketone formation. Not all metabolite structures are fully characterized and it is speculated that many metabolites exist in stereoisomers.10 Metabolites of ruxolitinib retain inhibitory activity against JAK1 and JAk2 to a lesser degree than the parent drug.11

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Route of elimination

Following oral administration of a single radiolabeled dose of ruxolitinib, the drug was mainly eliminated through metabolism. About 74% of the total dose was excreted in urine and 22% was excreted in feces,16 mostly in the form of hydroxyl and oxo metabolites of ruxolitinib.10 The unchanged parent drug accounted for less than 1% of the excreted total radioactivity.16

Half-life

The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of its metabolites is approximately 5.8 hours.16

Clearance

Ruxolitinib clearance (% coefficient of variation) is 17.7 L/h in women and 22.1 L/h in men with myelofibrosis. Drug clearance was 12.7 L/h (42%) in patients with polycythemia vera and 11.9 L/h (43%) in patients with acute graft-versus-host disease.16

Adverse Effects
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Toxicity

The oral LD50 was 250 mg/kg.18

Single doses of ruxolitinib up to 200 mg were tolerated well. Higher doses than recommended repeat doses are associated with myelosuppression, including leukopenia, anemia, and thrombocytopenia. There is no known antidote for overdoses with ruxolitinib: it is recommended that patients are given appropriate supportive treatment. Hemodialysis is not expected to enhance the elimination of ruxolitinib.16

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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AbacavirAbacavir may decrease the excretion rate of Ruxolitinib which could result in a higher serum level.
AbaloparatideThe therapeutic efficacy of Abaloparatide can be decreased when used in combination with Ruxolitinib.
AbametapirThe serum concentration of Ruxolitinib can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Ruxolitinib can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Ruxolitinib.
AbrocitinibThe metabolism of Abrocitinib can be decreased when combined with Ruxolitinib.
AcalabrutinibThe metabolism of Ruxolitinib can be decreased when combined with Acalabrutinib.
AcebutololRuxolitinib may increase the bradycardic activities of Acebutolol.
AceclofenacAceclofenac may decrease the excretion rate of Ruxolitinib which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Ruxolitinib which could result in a higher serum level.
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of ruxolitinib.
  • Exercise caution with St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum levels of ruxolitinib.
  • Take with or without food. A high-fat, high-calorie meal had negligible effects on the pharmacokinetics of ruxolitinib.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Ruxolitinib phosphate436LRU32H51092939-17-7JFMWPOCYMYGEDM-XFULWGLBSA-N
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
JakafiTablet10.0 mg/1OralIncyte Corporation2011-11-16Not applicableUS flag
JakafiTablet20.0 mg/1OralIncyte Corporation2011-11-16Not applicableUS flag
JakafiTablet5.0 mg/1OralIncyte Corporation2011-11-16Not applicableUS flag
JakafiTablet15.0 mg/1OralIncyte Corporation2011-11-16Not applicableUS flag
JakafiTablet25.0 mg/1OralIncyte Corporation2011-11-16Not applicableUS flag
JakaviTablet5 mgOralNovartis Europharm Limited2016-09-08Not applicableEU flag
JakaviTablet10 mgOralNovartis2015-04-15Not applicableCanada flag
JakaviTablet5 mgOralNovartis2012-07-19Not applicableCanada flag
JakaviTablet10 mgOralNovartis Europharm Limited2016-09-08Not applicableEU flag
JakaviTablet20 mgOralNovartis Europharm Limited2016-09-08Not applicableEU flag

Categories

ATC Codes
L01XE18 — Ruxolitinib
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as pyrrolo[2,3-d]pyrimidines. These are aromatic heteropolycyclic compounds containing a pyrrolo[2,3-d]pyrimidine ring system, which is an pyrrolopyrimidine isomers having the 3 ring nitrogen atoms at the 1-, 5-, and 7-positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Pyrrolopyrimidines
Sub Class
Pyrrolo[2,3-d]pyrimidines
Direct Parent
Pyrrolo[2,3-d]pyrimidines
Alternative Parents
Pyrimidines and pyrimidine derivatives / Pyrroles / Pyrazoles / Heteroaromatic compounds / Nitriles / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Aromatic heteropolycyclic compound / Azacycle / Azole / Carbonitrile / Heteroaromatic compound / Hydrocarbon derivative / Nitrile / Organic nitrogen compound / Organonitrogen compound / Organopnictogen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
pyrazoles, nitrile, pyrrolopyrimidine (CHEBI:66919)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
82S8X8XX8H
CAS number
941678-49-5
InChI Key
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[C@H](C1CCCC1)N1C=C(C=N1)C1=C2C=CNC2=NC=N1

References

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. [Article]
  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. [Article]
  3. Becker H, Engelhardt M, von Bubnoff N, Wasch R: Ruxolitinib. Recent Results Cancer Res. 2014;201:249-57. doi: 10.1007/978-3-642-54490-3_16. [Article]
  4. Ostojic A, Vrhovac R, Verstovsek S: Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol. 2011 Sep;7(9):1035-43. doi: 10.2217/fon.11.81. [Article]
  5. Ajayi S, Becker H, Reinhardt H, Engelhardt M, Zeiser R, von Bubnoff N, Wasch R: Ruxolitinib. Recent Results Cancer Res. 2018;212:119-132. doi: 10.1007/978-3-319-91439-8_6. [Article]
  6. Cao Y, Wei J, Zou L, Jiang T, Wang G, Chen L, Huang L, Meng F, Huang L, Wang N, Zhou X, Luo H, Mao Z, Chen X, Xie J, Liu J, Cheng H, Zhao J, Huang G, Wang W, Zhou J: Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020 Jul;146(1):137-146.e3. doi: 10.1016/j.jaci.2020.05.019. Epub 2020 May 26. [Article]
  7. La Rosee F, Bremer HC, Gehrke I, Kehr A, Hochhaus A, Birndt S, Fellhauer M, Henkes M, Kumle B, Russo SG, La Rosee P: The Janus kinase 1/2 inhibitor ruxolitinib in COVID-19 with severe systemic hyperinflammation. Leukemia. 2020 Jul;34(7):1805-1815. doi: 10.1038/s41375-020-0891-0. Epub 2020 Jun 9. [Article]
  8. Rosmarin D, Pandya AG, Lebwohl M, Grimes P, Hamzavi I, Gottlieb AB, Butler K, Kuo F, Sun K, Ji T, Howell MD, Harris JE: Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial. Lancet. 2020 Jul 11;396(10244):110-120. doi: 10.1016/S0140-6736(20)30609-7. [Article]
  9. Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME: Treatment of atopic dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J Allergy Clin Immunol. 2020 Feb;145(2):572-582. doi: 10.1016/j.jaci.2019.08.042. Epub 2019 Oct 17. [Article]
  10. Shilling AD, Nedza FM, Emm T, Diamond S, McKeever E, Punwani N, Williams W, Arvanitis A, Galya LG, Li M, Shepard S, Rodgers J, Yue TY, Yeleswaram S: Metabolism, excretion, and pharmacokinetics of [14C]INCB018424, a selective Janus tyrosine kinase 1/2 inhibitor, in humans. Drug Metab Dispos. 2010 Nov;38(11):2023-31. doi: 10.1124/dmd.110.033787. Epub 2010 Aug 10. [Article]
  11. Shi JG, Chen X, Emm T, Scherle PA, McGee RF, Lo Y, Landman RR, McKeever EG Jr, Punwani NG, Williams WV, Yeleswaram S: 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. [Article]
  12. Punwani N, Scherle P, Flores R, Shi J, Liang J, Yeleswaram S, Levy R, Williams W, Gottlieb A: Preliminary clinical activity of a topical JAK1/2 inhibitor in the treatment of psoriasis. J Am Acad Dermatol. 2012 Oct;67(4):658-64. doi: 10.1016/j.jaad.2011.12.018. Epub 2012 Jan 24. [Article]
  13. Spoerl S, Mathew NR, Bscheider M, Schmitt-Graeff A, Chen S, Mueller T, Verbeek M, Fischer J, Otten V, Schmickl M, Maas-Bauer K, Finke J, Peschel C, Duyster J, Poeck H, Zeiser R, von Bubnoff N: Activity of therapeutic JAK 1/2 blockade in graft-versus-host disease. Blood. 2014 Jun 12;123(24):3832-42. doi: 10.1182/blood-2013-12-543736. Epub 2014 Apr 7. [Article]
  14. Deshpande A, Reddy MM, Schade GO, Ray A, Chowdary TK, Griffin JD, Sattler M: Kinase domain mutations confer resistance to novel inhibitors targeting JAK2V617F in myeloproliferative neoplasms. Leukemia. 2012 Apr;26(4):708-15. doi: 10.1038/leu.2011.255. Epub 2011 Sep 16. [Article]
  15. Mughal TI, Girnius S, Rosen ST, Kumar S, Wiestner A, Abdel-Wahab O, Kiladjian JJ, Wilson WH, Van Etten RA: Emerging therapeutic paradigms to target the dysregulated Janus kinase/signal transducer and activator of transcription pathway in hematological malignancies. Leuk Lymphoma. 2014 Sep;55(9):1968-79. doi: 10.3109/10428194.2013.863307. Epub 2014 Feb 17. [Article]
  16. FDA Approved Drug Products: JAKAFI (ruxolitinib) tablets, for oral use [Link]
  17. Santa Cruz Biotechnology, Inc.: Ruxolitinib Safety Data Sheet [Link]
  18. LC Laboratories: Ruxolitinib Safety Data Sheet [Link]
  19. Drugs.com: Jakafi FDA Approval History [Link]
  20. Novartis: Novartis provides update on RUXCOVID study of ruxolitinib for hospitalized patients with COVID-19 [Link]
  21. BC Cancer - Ruxolitinib monograph [Link]
  22. Summary of Product Characteristics: Jakavi (ruxolitinib) oral tablets [Link]
  23. FDA Approved Drug Products: OPZELURA (ruxolitinib) cream, for topical use [Link]
KEGG Drug
D09959
PubChem Compound
25126798
PubChem Substance
175427129
ChemSpider
25027389
BindingDB
50355501
RxNav
1193326
ChEBI
66919
ChEMBL
CHEMBL1789941
ZINC
ZINC000043207851
PharmGKB
PA166123386
PDBe Ligand
RXT
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Ruxolitinib
PDB Entries
4u5j / 6vgl / 6vnk / 6wtn / 7f3g
FDA label
Download (399 KB)
MSDS
Download (210 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentPost Essential Thrombocythaemia Myelofibrosis (PET-MF) / Post Polycythaemia Myelofibrosis (PPV MF) / Primary Myelofibrosis (PMF)1
4Not Yet RecruitingTreatmentCytokine Storm / Hemophagocytic Lymphohistiocytoses1
4RecruitingPreventionGraft Versus Host Disease (cGvHD)1
4RecruitingTreatmentAcute Myeloid Leukemia (AML) / Graft Versus Host Disease (cGvHD) / Polycythemia Vera (PV) / Primary Myelofibrosis (PMF) / Thalassaemic disorders1
4RecruitingTreatmentEpstein Barr Virus Infections1
4RecruitingTreatmentHemophagocytic Syndrome (HPS) / T/NK-Cell Lymphoma1
4RecruitingTreatmentMyelofibrosis1
4RecruitingTreatmentSafety and Efficacy2
4RecruitingTreatmentThalassemia Major (TM)1
3Active Not RecruitingTreatmentGraft Versus Host Disease (cGvHD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
TabletOral10.0 mg/1
TabletOral15.0 mg/1
TabletOral20.0 mg/1
TabletOral25.0 mg/1
TabletOral5.0 mg/1
TabletOral19.8 mg
TabletOral6.6 mg
TabletOral15 mg
TabletOral20 mg
TabletOral5 mg
TabletOral
TabletOral10 mg
CreamTopical15 mg/1g
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7598257No2009-10-062027-12-24US flag
US8822481No2014-09-022028-06-12US flag
US8829013No2014-09-092028-06-12US flag
US9079912No2015-07-142026-12-12US flag
US8415362No2013-04-092027-12-24US flag
US8722693No2014-05-132028-06-12US flag
US9662335No2017-05-302026-12-12US flag
US10016429No2018-07-102028-06-12US flag
US9814722No2017-11-142026-12-12US flag
US9974790No2018-05-222026-12-12US flag
US10610530No2020-04-072028-06-12US flag
US10639310No2020-05-052026-12-12US flag
US10869870No2020-12-222031-05-20US flag
US10758543No2020-09-012031-05-20US flag
US11219624No2011-05-202031-05-20US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)86MSDS
boiling point (°C)592.6MSDS
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)3.91ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area83.18 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity98.01 m3·mol-1ChemAxon
Polarizability33.07 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

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Details1. Tyrosine-protein kinase JAK2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
In vitro, ruxolitinib inhibited JAK2 with a mean half-maximal inhibitory concentration (IC50) of 2.8 nmol/L (Yang & Keating, 2012).
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 adaptiv...
Gene Name
JAK2
Uniprot ID
O60674
Uniprot Name
Tyrosine-protein kinase JAK2
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. [Article]
  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. [Article]
  3. Ostojic A, Vrhovac R, Verstovsek S: Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol. 2011 Sep;7(9):1035-43. doi: 10.2217/fon.11.81. [Article]
Details2. Tyrosine-protein kinase JAK1
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
In vitro, ruxolitinib inhibited JAK1 with a mean half-maximal inhibitory concentration (IC50) of 3.3 nmol/L (Yang & Keating, 2012).
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
Uniprot Name
Tyrosine-protein kinase JAK1
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. [Article]
  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. [Article]
  3. Ostojic A, Vrhovac R, Verstovsek S: Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol. 2011 Sep;7(9):1035-43. doi: 10.2217/fon.11.81. [Article]
Details3. Tyrosine-protein kinase JAK3
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
In vitro, ruxolitinib inhibited JAK3 with a mean half-maximal inhibitory concentration (IC50) of 428 nmol/L (Yang & Keating, 2012).
General Function
Protein tyrosine kinase activity
Specific Function
Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a...
Gene Name
JAK3
Uniprot ID
P52333
Uniprot Name
Tyrosine-protein kinase JAK3
Molecular Weight
125097.565 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. [Article]
  2. Ostojic A, Vrhovac R, Verstovsek S: Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol. 2011 Sep;7(9):1035-43. doi: 10.2217/fon.11.81. [Article]
Details4. Non-receptor tyrosine-protein kinase TYK2
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
Curator comments
In vitro, ruxolitinib inhibited TYK2 with a mean half-maximal inhibitory concentration (IC50) of 19 nmol/L (Yang & Keating, 2012).
General Function
Protein tyrosine kinase activity
Specific Function
Probably involved in intracellular signal transduction by being involved in the initiation of type I IFN signaling. Phosphorylates the interferon-alpha/beta receptor alpha chain.
Gene Name
TYK2
Uniprot ID
P29597
Uniprot Name
Non-receptor tyrosine-protein kinase TYK2
Molecular Weight
133648.77 Da
References
  1. Ostojic A, Vrhovac R, Verstovsek S: Ruxolitinib: a new JAK1/2 inhibitor that offers promising options for treatment of myelofibrosis. Future Oncol. 2011 Sep;7(9):1035-43. doi: 10.2217/fon.11.81. [Article]
  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. [Article]

Enzymes

Details1. Cytochrome P450 3A4
Kind
Protein
Organism
Humans
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
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. [Article]
  2. Becker H, Engelhardt M, von Bubnoff N, Wasch R: Ruxolitinib. Recent Results Cancer Res. 2014;201:249-57. doi: 10.1007/978-3-642-54490-3_16. [Article]
  3. Ajayi S, Becker H, Reinhardt H, Engelhardt M, Zeiser R, von Bubnoff N, Wasch R: Ruxolitinib. Recent Results Cancer Res. 2018;212:119-132. doi: 10.1007/978-3-319-91439-8_6. [Article]
  4. FDA Approved Drug Products: JAKAFI (ruxolitinib) tablets, for oral use [Link]
Details2. Cytochrome P450 2C9
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Steroid 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 oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Umehara K, Huth F, Jin Y, Schiller H, Aslanis V, Heimbach T, He H: Drug-drug interaction (DDI) assessments of ruxolitinib, a dual substrate of CYP3A4 and CYP2C9, using a verified physiologically based pharmacokinetic (PBPK) model to support regulatory submissions. Drug Metab Pers Ther. 2019 May 30;34(2). pii: /j/dmdi.ahead-of-print/dmpt-2018-0042/dmpt-2018-0042.xml. doi: 10.1515/dmpt-2018-0042. [Article]
  2. FDA Approved Drug Products: JAKAFI (ruxolitinib) tablets, for oral use [Link]

Carriers

Details1. Serum albumin
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: JAKAFI (ruxolitinib) tablets, for oral use [Link]

Drug created at May 13, 2013 18:21 / Updated at August 14, 2022 00:07