Ruxolitinib

Identification

Name

Ruxolitinib

Accession Number

DB08877

Description

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 Available as oral tablets, ruxolitinib is commonly marketed under the trade name Jakafi. 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 Ruxolitinib was not approved as a treatment for COVID-19. The topical formulation of ruxolitinib was investigated to treat vitiligo,⁸ atopic dermatitis,⁹ and psoriasis,¹² where it showed promising preliminary results in improving the symptoms of inflammatory skin conditions.

Type

Small Molecule

Groups

Approved

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Ruxolitinib (DB08877)

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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

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Indication

Ruxolitinib is indicated for the treatment of inte1mediate or high-risk myelofibrosis (MF), including prima1y MF, post-polycythemia vera MF and post-essential thrombocythemia MF in adults.¹⁶ It is also indicated to treat disease-related splenomegaly or symptoms in adult patients with these conditions.²²

Ruxolitinib is indicated for the treatment of polycythemia vera (PV) in adults who have had an inadequate response to or are intolerant of hydroxyurea.¹⁶

Ruxolitinib is indicated for the treatment of steroid-refracto1y acute graft-versus-host disease (GVHD) in adult and pediatric patients 12 years and older.¹⁶

Associated Conditions

• Graft Versus Host Disease, Acute
• Post Essential Thrombocythaemia Myelofibrosis
• Post Polycythemia Vera Myelofibrosis
• Primary Myelofibrosis
• High risk Myelofibrosis
• Intermediate risk Myelofibrosis
• Refractory Polycythemia vera

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

Target	Actions	Organism
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 (C_max) increases proportionally. C_max ranged from 205 nM to 7100 nM and AUC ranged from 862 nM x hr to 30700 nM x hr. T_max 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

Hover over products below to view reaction partners

• Ruxolitinib
  • Ruxolitinib M18 metabolite
  • Ruxolitinib M49 metabolite
  • Ruxolitinib M16 metabolite
    • Ruxolitinib M9 metabolite

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

Affected organisms

• Humans and other mammals

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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Abacavir	Abacavir may decrease the excretion rate of Ruxolitinib which could result in a higher serum level.
Abaloparatide	The therapeutic efficacy of Abaloparatide can be decreased when used in combination with Ruxolitinib.
Abametapir	The serum concentration of Ruxolitinib can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Ruxolitinib can be increased when combined with Abatacept.
Abciximab	The risk or severity of bleeding can be increased when Abciximab is combined with Ruxolitinib.
Abiraterone	The metabolism of Ruxolitinib can be decreased when combined with Abiraterone.
Acalabrutinib	The metabolism of Ruxolitinib can be decreased when combined with Acalabrutinib.
Acebutolol	Ruxolitinib may increase the bradycardic activities of Acebutolol.
Aceclofenac	Aceclofenac may decrease the excretion rate of Ruxolitinib which could result in a higher serum level.
Acemetacin	Acemetacin 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

Ingredient	UNII	CAS	InChI Key
Ruxolitinib phosphate	436LRU32H5	1092939-17-7	JFMWPOCYMYGEDM-XFULWGLBSA-N

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Jakafi	Tablet	25.0 mg/1	Oral	Incyte Corporation	2011-11-16	Not applicable
Jakafi	Tablet	10.0 mg/1	Oral	Incyte Corporation	2011-11-16	Not applicable
Jakafi	Tablet	20.0 mg/1	Oral	Incyte Corporation	2011-11-16	Not applicable
Jakafi	Tablet	5.0 mg/1	Oral	Incyte Corporation	2011-11-16	Not applicable
Jakafi	Tablet	15.0 mg/1	Oral	Incyte Corporation	2011-11-16	Not applicable
Jakavi	Tablet	5 mg	Oral	Novartis Europharm Limited	2016-09-08	Not applicable
Jakavi	Tablet	10 mg	Oral	Novartis Europharm Limited	2016-09-08	Not applicable
Jakavi	Tablet	20 mg	Oral	Novartis Europharm Limited	2016-09-08	Not applicable
Jakavi	Tablet		Oral	Novartis	2012-07-19	Not applicable
Jakavi	Tablet	15 mg	Oral	Novartis Europharm Limited	2016-09-08	Not applicable

Categories

ATC Codes

L01XE18 — Ruxolitinib

• L01XE — Protein kinase inhibitors
• L01X — OTHER ANTINEOPLASTIC AGENTS
• L01 — ANTINEOPLASTIC AGENTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

Drug Categories

• Antineoplastic Agents
• Antineoplastic and Immunomodulating Agents
• Cancer immunotherapy
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2C9 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
• Cytochrome P-450 Substrates
• Drugs that are Mainly Renally Excreted
• Immunosuppressive Agents
• Immunotherapy
• Janus Kinases, antagonists & inhibitors
• Kinase Inhibitor
• Myelosuppressive Agents
• Narrow Therapeutic Index Drugs
• Protein Kinase Inhibitors
• Tyrosine Kinase Inhibitors

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)

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. [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]
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. [PubMed:24756798]
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. [PubMed:21919691]
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. [PubMed:30069628]
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. [PubMed:32470486]
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. [PubMed:32518419]
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. [PubMed:32653055]
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. [PubMed:31629805]
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. [PubMed:20699411]
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. [PubMed:21602517]
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. [PubMed:22281165]
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. [PubMed:24711661]
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. [PubMed:21926964]
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. [PubMed:24206094]
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]

External Links

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

AHFS Codes

• 10:00.00 — Antineoplastic Agents

PDB Entries

4u5j / 6vgl / 6vnk

FDA label

Download (399 KB)

MSDS

Download (210 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Post Essential Thrombocythaemia Myelofibrosis (PET-MF) / Post Polycythaemia Myelofibrosis (PPV MF) / Primary Myelofibrosis (PMF)	1
4	Recruiting	Prevention	Graft Versus Host Disease (GVHD)	1
4	Recruiting	Treatment	Chronic Idiopathic Myelofibrosis / Post Essential Thrombocythaemia Myelofibrosis / Post Polycythemia Vera Myelofibrosis / Primary Myelofibrosis / Steroid Refractory Graft Versus Host Disease	1
4	Recruiting	Treatment	Safety and Efficacy	1
4	Recruiting	Treatment	Thalassemia Major (TM)	1
3	Active Not Recruiting	Treatment	Corticosteroid Refractory Acute Graft vs Host Disease	1
3	Active Not Recruiting	Treatment	Graft Versus Host Disease (GVHD) / Graft-versus-host Disease (GVHD)	1
3	Active Not Recruiting	Treatment	Non-segmental Vitiligo	2
3	Completed	Treatment	Agnogenic Myeloid Metaplasia	2
3	Completed	Treatment	Atopic Dermatitis (AD)	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Tablet	Oral	10.0 mg/1
Tablet	Oral	15.0 mg/1
Tablet	Oral	20.0 mg/1
Tablet	Oral	25.0 mg/1
Tablet	Oral	5.0 mg/1
Tablet	Oral	10 mg
Tablet	Oral	15 mg
Tablet	Oral	20 mg
Tablet	Oral	5 mg
Tablet	Oral

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US7598257	No	2009-10-06	2027-12-24
US8822481	No	2014-09-02	2028-06-12
US8829013	No	2014-09-09	2028-06-12
US9079912	No	2015-07-14	2026-12-12
US8415362	No	2013-04-09	2027-12-24
US8722693	No	2014-05-13	2028-06-12
US9662335	No	2017-05-30	2026-12-12
US10016429	No	2018-07-10	2028-06-12
US9814722	No	2017-11-14	2026-12-12

Properties

State

Solid

Experimental Properties

Property	Value	Source
melting point (°C)	86	MSDS
boiling point (°C)	592.6	MSDS
water solubility	Soluble in aqueous buffers across a pH of 1-8	FDA label

Predicted Properties

Property	Value	Source
Water Solubility	0.116 mg/mL	ALOGPS
logP	2.94	ALOGPS
logP	2.48	ChemAxon
logS	-3.4	ALOGPS
pKa (Strongest Acidic)	13.89	ChemAxon
pKa (Strongest Basic)	5.51	ChemAxon
Physiological Charge	0	ChemAxon
Hydrogen Acceptor Count	4	ChemAxon
Hydrogen Donor Count	1	ChemAxon
Polar Surface Area	83.18 Å2	ChemAxon
Rotatable Bond Count	4	ChemAxon
Refractivity	98.01 m3·mol-1	ChemAxon
Polarizability	33.04 Å3	ChemAxon
Number of Rings	4	ChemAxon
Bioavailability	1	ChemAxon
Rule of Five	Yes	ChemAxon
Ghose Filter	Yes	ChemAxon
Veber's Rule	No	ChemAxon
MDDR-like Rule	No	ChemAxon

Predicted ADMET Features

Property	Value	Probability
Human Intestinal Absorption	+	1.0
Blood Brain Barrier	+	0.9673
Caco-2 permeable	-	0.5198
P-glycoprotein substrate	Non-substrate	0.7838
P-glycoprotein inhibitor I	Non-inhibitor	0.8228
P-glycoprotein inhibitor II	Inhibitor	0.7092
Renal organic cation transporter	Non-inhibitor	0.5098
CYP450 2C9 substrate	Non-substrate	0.8394
CYP450 2D6 substrate	Non-substrate	0.8075
CYP450 3A4 substrate	Non-substrate	0.6535
CYP450 1A2 substrate	Inhibitor	0.6426
CYP450 2C9 inhibitor	Non-inhibitor	0.7731
CYP450 2D6 inhibitor	Non-inhibitor	0.9208
CYP450 2C19 inhibitor	Non-inhibitor	0.6689
CYP450 3A4 inhibitor	Non-inhibitor	0.6655
CYP450 inhibitory promiscuity	High CYP Inhibitory Promiscuity	0.5753
Ames test	AMES toxic	0.5681
Carcinogenicity	Non-carcinogens	0.9308
Biodegradation	Not ready biodegradable	0.9917
Rat acute toxicity	2.5724 LD50, mol/kg	Not applicable
hERG inhibition (predictor I)	Weak inhibitor	0.633
hERG inhibition (predictor II)	Non-inhibitor	0.8772

ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	Not Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	Not Available

Targets

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Binding Properties

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Property	Measurement	pH	Temperature (°C)	References
EC 50 (nM)	12	N/A	N/A	22698084
IC 50 (nM)	2.8	N/A	N/A	22591402
IC 50 (nM)	3	N/A	N/A	21106455
IC 50 (nM)	6.85	N/A	N/A	23061660
Kd (nM)	0.036	N/A	N/A	22037378
Ki (nM)	0.1	N/A	N/A	22698084
Ki (nM)	0.24	N/A	N/A	23061660

Details

Binding Properties1. 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. [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]
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. [PubMed:21919691]

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. [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]
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. [PubMed:21919691]

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. [PubMed:23061804]
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. [PubMed:21919691]

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. [PubMed:21919691]
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]

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Drug created on May 13, 2013 18:21 / Updated on April 13, 2021 00:29