Ruxolitinib phosphate
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MedKoo CAT#: 120209

CAS#: 1092939-17-7 (phosphate)

Description: Ruxolitinib, also known as INC424 and INCB18424 or INCB018424, is an orally bioavailable Janus-associated kinase (JAK) inhibitor with potential antineoplastic and immunomodulating activities. Ruxolitinib specifically binds to and inhibits protein tyrosine kinases JAK 1 and 2, which may lead to a reduction in inflammation and an inhibition of cellular proliferation. The JAK-STAT (signal transducer and activator of transcription) pathway plays a key role in the signaling of many cytokines and growth factors and is involved in cellular proliferation, growth, hematopoiesis, and the immune response; JAK kinases may be upregulated in inflammatory diseases, myeloproliferative disorders, and various malignancies.


Chemical Structure

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Ruxolitinib phosphate
CAS# 1092939-17-7 (phosphate)

Theoretical Analysis

MedKoo Cat#: 120209
Name: Ruxolitinib phosphate
CAS#: 1092939-17-7 (phosphate)
Chemical Formula: C17H21N6O4P
Exact Mass: 404.13619
Molecular Weight: 404.37
Elemental Analysis:

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Related CAS #: 941678-49-5 (free base)   1092939-17-7 (phosphate)    

Synonym: INCB018424; INCB 018424; INCB-018424; INC424; INC-424; INC424; INCB18424; INCB 18424; INCB-18424; trade name: Jakafi and Jakavi

IUPAC/Chemical Name: (R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile phosphate

InChi Key: JFMWPOCYMYGEDM-XFULWGLBSA-N

InChi Code: InChI=1S/C17H18N6.H3O4P/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;1-5(2,3)4/h6,8-12,15H,1-5H2,(H,19,20,21);(H3,1,2,3,4)/t15-;/m1./s1

SMILES Code: N#CC[C@@H](N1N=CC(C2=C3C(NC=C3)=NC=N2)=C1)C4CCCC4.O=P(O)(O)O

Appearance: white solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: Ruxolitinib phosphate (INCB018424 phosphate) is a potent JAK1/2 inhibitor with IC50s of 3.3 nM/2.8 nM, respectively.
In vitro activity: In this report, the preclinical characterization of INCB018424, a potent, selective, and orally bioavailable inhibitor of JAK1 and JAK2 was described. The results shown in Table 1 demonstrated the potent in vitro activity of INCB018424 on wild-type JAK1 and JAK2. Although there is no biochemical basis for differential activity of ATP-competitive kinase inhibitors on the mutant JAK2V617F, the effect of INCB018424 on cells driven by JAK2V617F is not known. To better understand the consequences of JAK1/2 inhibition in cells expressing mutated JAK2, Ba/F3-EpoR-JAK2V617F cells were treated with INCB018424 and a viable cell number was assessed after 48 hours. A dose-dependent reduction in viability was observed with an IC50 of 126nM (Figure 1D square). Growth of HEL cells was also affected by INCB018424 with a 50% effective concentration (EC50) of 186nM. Unlike the BaF/3 cells, HEL cell proliferation was not completely inhibited by INCB018424 (Figure 1B), even though pSTAT3 and pSTAT5 were completely absent at concentrations more than 100nM (Figure 1D triangle) suggesting that the proliferation in these cells is not entirely JAK2V617F dependent. Importantly, the sensitivity of these cell lines to the effects of INCB018424 was in stark contrast to the lack of effect on TF-1 or BaF/3 cells transformed with the BCR-ABL oncoprotein. In these cells, no significant effect on viability was observed, consistent with the selective nature of INCB018424 (Figure 1D, diamond and open square). Likewise, 2 cell lines expressing activating mutations in c-KIT (HMC1.1 and HMC1.2) were also resistant (data not shown). INCB018424 also had no effect on BCRABL signaling, as demonstrated by an inability to reduce ABL-mediated pSTAT5, in contrast to imatinib. It was demonstrated that, at nanomolar concentrations, INCB018424 inhibits JAK2V617F, STAT5, and ERK1/2 phosphorylation resulting in reduced cellular proliferation and the induction of apoptosis by JAK2V617F+ Ba/F3 cells. Blood. 2010 Apr 15; 115(15): 3109–3117. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3953826/
In vivo activity: 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+CD8+ splenic DCs. Indeed, lower expression levels of CD40, CD80, CD86 as well as MHC I and II molecules were detected in ruxolitinib-challenged animals (Figure 4A). 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. OVA is usually taken up by DCs in vivo and then cross-presented on MHC class I molecules. Analysis of transferred CFSE-labeled OT-I T cells revealed reduced proliferation (Figure 4B-C), CD25 expression (Figure 4D-E), and IFN-γ production (Figure 4F-G) in mice pretreated with ruxolitinib. The effects of ruxolitinib on the induction of cytotoxic activity of CD8+ T cells in a non–TCR-transgenic setting were evaluated. To this end, the in vivo cytotoxic T-cell response against OVA in C57/BL6N mice primed with OVA/CpG either exposed to ruxolitinib or vehicle was quantified. Using this assay, it has been shown that ruxolitinib markedly reduces OVA-specific cytotoxic activity (Figure 4H). Blood. 2013 Aug 15;122(7):1192-202. https://pubmed.ncbi.nlm.nih.gov/23770777/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 50.8 125.66
Ethanol 6.5 16.07

Preparing Stock Solutions

The following data is based on the product molecular weight 404.37 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, Caulder E, Wen X, Li Y, Waeltz P, Rupar M, Burn T, Lo Y, Kelley J, Covington M, Shepard S, Rodgers JD, Haley P, Kantarjian H, Fridman JS, Verstovsek S. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010 Apr 15;115(15):3109-17. doi: 10.1182/blood-2009-04-214957. Epub 2010 Feb 3. PMID: 20130243; PMCID: PMC3953826. 2. Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, Wolf D, Brossart P. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013 Aug 15;122(7):1192-202. doi: 10.1182/blood-2013-03-484642. Epub 2013 Jun 14. PMID: 23770777.
In vitro protocol: 1. Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, Caulder E, Wen X, Li Y, Waeltz P, Rupar M, Burn T, Lo Y, Kelley J, Covington M, Shepard S, Rodgers JD, Haley P, Kantarjian H, Fridman JS, Verstovsek S. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010 Apr 15;115(15):3109-17. doi: 10.1182/blood-2009-04-214957. Epub 2010 Feb 3. PMID: 20130243; PMCID: PMC3953826. 2. Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, Wolf D, Brossart P. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013 Aug 15;122(7):1192-202. doi: 10.1182/blood-2013-03-484642. Epub 2013 Jun 14. PMID: 23770777.
In vivo protocol: 1. Quintás-Cardama A, Vaddi K, Liu P, Manshouri T, Li J, Scherle PA, Caulder E, Wen X, Li Y, Waeltz P, Rupar M, Burn T, Lo Y, Kelley J, Covington M, Shepard S, Rodgers JD, Haley P, Kantarjian H, Fridman JS, Verstovsek S. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood. 2010 Apr 15;115(15):3109-17. doi: 10.1182/blood-2009-04-214957. Epub 2010 Feb 3. PMID: 20130243; PMCID: PMC3953826. 2. Heine A, Held SA, Daecke SN, Wallner S, Yajnanarayana SP, Kurts C, Wolf D, Brossart P. The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. Blood. 2013 Aug 15;122(7):1192-202. doi: 10.1182/blood-2013-03-484642. Epub 2013 Jun 14. PMID: 23770777.

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1: Santos FP, Verstovsek S. Efficacy of ruxolitinib for myelofibrosis. Expert Opin Pharmacother. 2014 Jul;15(10):1465-73. doi: 10.1517/14656566.2014.923404. Epub 2014 May 24. Review. PubMed PMID: 24856675.

2: Molica M, Serrao A, Saracino R, Zacheo I, Stingone C, Alimena G, Breccia M. Disappearance of fibrosis in secondary myelofibrosis after ruxolitinib treatment: new endpoint to achieve? Ann Hematol. 2014 Nov;93(11):1951-2. doi: 10.1007/s00277-014-2096-y. Epub 2014 May 7. Review. PubMed PMID: 24801017.

3: Becker H, Engelhardt M, von Bubnoff N, Wäsch R. Ruxolitinib. Recent Results Cancer Res. 2014;201:249-57. doi: 10.1007/978-3-642-54490-3_16. Review. PubMed PMID: 24756798.

4: Swaim SJ. Ruxolitinib for the treatment of primary myelofibrosis. Am J Health Syst Pharm. 2014 Mar 15;71(6):453-62. doi: 10.2146/ajhp120602. Review. PubMed PMID: 24589536.

5: Mesa RA, Cortes J. Optimizing management of ruxolitinib in patients with myelofibrosis: the need for individualized dosing. J Hematol Oncol. 2013 Oct 22;6:79. doi: 10.1186/1756-8722-6-79. Review. PubMed PMID: 24283870; PubMed Central PMCID: PMC4222119.

6: Kantarjian HM, Silver RT, Komrokji RS, Mesa RA, Tacke R, Harrison CN. Ruxolitinib for myelofibrosis--an update of its clinical effects. Clin Lymphoma Myeloma Leuk. 2013 Dec;13(6):638-45. doi: 10.1016/j.clml.2013.09.006. Epub 2013 Oct 2. Review. PubMed PMID: 24238036.

7: Harrison C, Mesa R, Ross D, Mead A, Keohane C, Gotlib J, Verstovsek S. Practical management of patients with myelofibrosis receiving ruxolitinib. Expert Rev Hematol. 2013 Oct;6(5):511-23. doi: 10.1586/17474086.2013.827413. Epub 2013 Oct 2. Review. PubMed PMID: 24083419.

8: Wade R, Rose M, Neilson AR, Stirk L, Rodriguez-Lopez R, Bowen D, Craig D, Woolacott N. Ruxolitinib for the treatment of myelofibrosis: a NICE single technology appraisal. Pharmacoeconomics. 2013 Oct;31(10):841-52. doi: 10.1007/s40273-013-0083-0. Review. PubMed PMID: 23996108.

9: Lemal R, Robin M, Ravinet A, Cacheux V, Guièze R, Bay JO. [Ruxolitinib prescription in myelofibrosis]. Bull Cancer. 2013 Sep;100(9):897-902. doi: 10.1684/bdc.2013.1792. Review. French. PubMed PMID: 23985569.

10: Kremyanskaya M, Atallah EL, Hoffman R, Mascarenhas JO. Clarifying the use of ruxolitinib in patients with myelofibrosis. Oncology (Williston Park). 2013 Jul;27(7):706-14. Review. Erratum in: Oncology (Williston Park). 2013 Aug;27(8):737. PubMed PMID: 23977767.

11: Mascarenhas J, Hoffman R. A comprehensive review and analysis of the effect of ruxolitinib therapy on the survival of patients with myelofibrosis. Blood. 2013 Jun 13;121(24):4832-7. doi: 10.1182/blood-2013-02-482232. Epub 2013 Apr 9. Review. PubMed PMID: 23570800.

12: Verstovsek S. Ruxolitinib: an oral Janus kinase 1 and Janus kinase 2 inhibitor in the management of myelofibrosis. Postgrad Med. 2013 Jan;125(1):128-35. doi: 10.3810/pgm.2013.01.2628. Review. PubMed PMID: 23391678.

13: Ganetsky A. Ruxolitinib: a new treatment option for myelofibrosis. Pharmacotherapy. 2013 Jan;33(1):84-92. doi: 10.1002/phar.1165. Review. PubMed PMID: 23307549.

14: Vaddi K, Sarlis NJ, Gupta V. Ruxolitinib, an oral JAK1 and JAK2 inhibitor, in myelofibrosis. Expert Opin Pharmacother. 2012 Nov;13(16):2397-407. doi: 10.1517/14656566.2012.732998. Epub 2012 Oct 10. Review. PubMed PMID: 23051187.

15: Mascarenhas J, Mughal TI, Verstovsek S. Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Curr Med Chem. 2012;19(26):4399-413. Review. PubMed PMID: 22830345; PubMed Central PMCID: PMC3480698.

16: Ruxolitinib (Jakafi) for myelofibrosis. Med Lett Drugs Ther. 2012 Apr 2;54(1387):27-8. Review. PubMed PMID: 22469651.

17: Ostojic A, Vrhovac R, Verstovsek S. Ruxolitinib for the treatment of myelofibrosis. Drugs Today (Barc). 2011 Nov;47(11):817-27. doi: 10.1358/dot.2011.47.11.1708829. Review. PubMed PMID: 22146225.

18: Naqvi K, Verstovsek S, Kantarjian H, Ravandi F. A potential role of ruxolitinib in leukemia. Expert Opin Investig Drugs. 2011 Aug;20(8):1159-66. doi: 10.1517/13543784.2011.589383. Epub 2011 Jun 3. Review. PubMed PMID: 21635221; PubMed Central PMCID: PMC4143907.



Additional Information

Ruxolitinib is a drug being investigated for the treatment of myeloproliferative diseases, plaque psoriasis, and various types of cancer. It is a Janus kinase inhibitor with selectivity for subtypes 1 and 2 of this enzyme.  Roxolitinib is being marketed by Incyte Pharmaceuticals and Novartis under the trade name Jakafi. Results from Phase II clinical trials suggest that the drug can substantially improve symptoms and reduce spleen size in myelofibrosis patients, but it has not been shown to produce remission.[4] As of February 2011, it is undergoing Phase III trials studying myelofibrosis  and polycythemia vera. In June 2011, it was announced that both phase III trials of ruxolitinib in the treatment of myelofibrosis (COMFORT-I and -II) met their primary endpoints of a significant increase in number of patients experiencing at least 35% reduction of spleen volume. In November 2011, Ruxolitinib was approved by the U.S. Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis based on results of the COMFORT-I and COMFORT-II Trials. (source: http://en.wikipedia.org/wiki/Ruxolitinib).