Tofacitinib (CP-690550) Citrate Licensed by Pfizer

Tofacitinib citrate (CP-690550 citrate) is a novel inhibitor of JAK3 with IC50 of 1 nM, 20- to 100-fold less potent against JAK2 and JAK1.

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Tofacitinib (CP-690550) Citrate Chemical Structure

Tofacitinib (CP-690550) Citrate Chemical Structure
Molecular Weight: 504.49

Validation & Quality Control

Customer Reviews(4)

Quality Control & MSDS

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Tofacitinib (CP-690550) Citrate is available in the following compound libraries:

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Product Information

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  • Tofacitinib (CP-690550) Citrate Mechanism

Product Description

Biological Activity

Description Tofacitinib citrate (CP-690550 citrate) is a novel inhibitor of JAK3 with IC50 of 1 nM, 20- to 100-fold less potent against JAK2 and JAK1.
Targets JAK3 JAK2 JAK1 ROCK2 LCK

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IC50 1 nM [1] 20 nM [4] 112 nM [4] 3.4 μM [4] 3.87 μM [4]
In vitro Tofacitinib citrate inhibits IL-2-mediated human T cell blast proliferation and IL-15-induced CD69 expression with IC50 of 11 nM and 48 nM, respectively. Tofacitinib citrate prevents mixed lymphocyte reaction with IC50 of 87 nM. Tofacitinib citrate treatment of murine factor-dependent cell Patersen–erythropoietin receptor (FDCP-EpoR) cells harboring human wild-type or V617F JAK2 leads to prevention of cell proliferation with IC50 of 2.1 µM and 0.25 µM, respectively. Tofacitinib citrate inhibits interleukin-6-induced phosphorylation of STAT1 and STAT3 with IC50 of 23 nM and 77 nM, respectively. Moreover, Tofacitinib citrate generates a significant pro-apoptotic effect on murine FDCP-EpoR cells carrying JAK2VV617F, whereas a lesser effect is observed for cells carrying wild-type JAK2. This activity is coupled with the inhibition of phosphorylation of the key JAK2V617F-dependent downstream signaling effectors signal transducer and activator of transcription (STAT)3, STAT5, and v-akt murine thymoma viral oncogene homolog (AKT). [2] Additionally, Tofacitinib citrate prevents IL-15-induced CD69 expression in human and cynomolgus monkey NK and CD8+ T cells in vitro. [3]
In vivo Tofacitinib citrate decrease a delayed-type hyper-sensitivity response and extended cardiac allograft survival in murine models. Furthermore, Tofacitinib citrate treatment of ex-vivo-expanded erythroid progenitors from JAK2V617F-positive PV patients results in specific, antiproliferative (IC50 = 0.2 μM) and pro-apoptotic activity. In contrast, expanded progenitors from healthy controls are less sensitive to Tofacitinib citrate in proliferation (IC50 > 1.0 μM), and apoptosis assays.[2] During 2 weeks of Tofacitinib citrate dosing at 10 and 30 mg/kg/d, a significant, time-dependent decrease in NK cell numbers relative to vehicle treatment is observed. Effector memory CD8+ cell numbers in the Tofacitinib citrate-treated group are 55% less than those observed in animals treated with vehicle.[3]
Features

Protocol(Only for Reference)

Kinase Assay: [1]

Enzyme assays The JAK1, JAK2, and JAK3 kinase assays utilize a protein expressed in baculovirus-infected SF9 cells (a fusion protein of GST and the catalytic domain of human JAK enzyme) purified by affinity chromatography on glutathione−Sepharose. The substrate for the reaction is polyglutamic acid-tyrosine [PGT (4:1)], coated onto Nunc Maxi Sorp plates at 100 μg/mL overnight at 37 °C. The plates are washed three times, and JAK enzyme is added to the wells, which contained 100 μL of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCl, 24 mM MgCl2) + ATP + 1 mM sodium orthovanadate). For Tofacitinib citrate, it is also added for kinase assay at different doses. After incubation at room temperature for 30 min, the plates are washed three times. The level of phosphorylated tyrosine in a given well is determined by standard ELISA assay utilizing an anti-phosphotyrosine antibody.

Cell Assay: [2]

Cell lines FDCP-EpoR JAK2WT and JAK2V617F cell lines
Concentrations 0-4 μM
Incubation Time 72 hours
Method Determination of growth inhibition by Tofacitinib citrate is performed using identical culture conditions for both FDCP-EpoR JAK2WT and JAK2V617F cell lines. Briefly, 1 × 105 cells/mL are cultured in 96-well flat-bottom plates at 37 °C in a humidified 5% CO2 atmosphere using RPMI 1640 supplemented with 1.25% FCS, and 5% WEHI supernatant. Decreased FCS concentration is necessary to prevent binding between Tofacitinib citrate and serum proteins. Growth inhibition assays are terminated by addition of 20 μL CellTiter96 One Solution Reagent. Flat-bottom plates are incubated for an additional 3 hours for MTT assay. Absorbance is determined at 595 nm on a BioTek Synergy-HT microplate reader. Results are the average standard deviation of three independent determinations.

Animal Study: [2]

Animal Models Mauritius-origin adult cynomolgus monkeys
Formulation 0.5% methylcellulose in distilled water
Dosages 10, 30 mg/kg/d
Administration Oral gavage
Solubility 0.5% methylcellulose, , 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
1

References

[1] Flanagan ME, et al. J Med Chem, 2010, 53(24), 8468-8484.

[2] Manshouri T, et al. Cancer Sci, 2008, 99(6), 1265-1273.

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Clinical Trial Information( data from http://clinicaltrials.gov)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT01184092 Completed Rheumatoid Arthritis Pfizer 2010-08 Phase 1

Chemical Information

Download Tofacitinib (CP-690550) Citrate SDF
Molecular Weight (MW) 504.49
Formula

C16H20N6O.C6H8O7

CAS No. 540737-29-9
Storage 3 years -20℃Powder
6 months-80℃in DMSO
Synonyms
Solubility (25°C) * In vitro DMSO 100 mg/mL (198 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose, 30 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile citrate

Research Area

Customer Reviews (4)


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Rating
Source Dr. Akihiko Yoshimura of Akihiko Yoshimura. Tofacitinib (CP-690550) Citrate purchased from Selleck
Method real-time PCR, ELISA, Western blot
Cell Lines hind paws cells of mice
Concentrations 15mg/kg/day
Incubation Time 2 weeks
Results STAT3-inhibition antagonizes arthritis effects in vivo.

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Rating
Source Dr. Akihiko Yoshimura of Akihiko Yoshimura. Tofacitinib (CP-690550) Citrate purchased from Selleck
Method Histopathology, fluorescent immunohistochemistry
Cell Lines DBA/J1 male mice
Concentrations 15mg/kg/day
Incubation Time 2 weeks
Results Joint destruction seen in the CIA model was rescued by CP690,550 treatment

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Rating
Source Dr. Akihiko Yoshimura of Akihiko Yoshimura. Tofacitinib (CP-690550) Citrate purchased from Selleck
Method Immunoblotting, real-time PCR
Cell Lines MC3T3-E1 cells
Concentrations 0-1000 nM
Incubation Time 24 h
Results The STAT3 inhibitor CP690,550 inhibits arthritis in vivo and the expression of IL-6 cytokine family in vitro.

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Rating
Source Biochem Biophy Res Commun 2010 402, 500–506. Tofacitinib (CP-690550) Citrate purchased from Selleck
Method RT-PCR, ELISA, TTC staining, Neurological assessment
Cell Lines γδT cells and activated memory T cells
Concentrations 10 μM
Incubation Time
Results CP-690550 efficiently suppressed IL-17 production by γδT cells as well as memory CD4+T cells.We investigated the effect of CP-690550 in ischemic brain damage in mice. CP-690550 or vehicle was injected intra-peritoneally after I/R. The degree of CBF reduction was similar in the two groups (Fig. B). As shown in Fig. 1C, the functional neurological deficit induced by I/R surgery was significantly improved in mice receiving CP-690550 7 days after MCAO compared to control mice. Infarct size was smaller in mice treated with CP-690550 3 days after MCAO than in untreated mice, as shown in Fig. D

Product Citations (6)

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