1. Epigenetics
    Stem Cell/Wnt
    JAK/STAT Signaling
  2. JAK

Tofacitinib citrate (Synonyms: Tasocitinib citrate; CP-690550 citrate)

Cat. No.: HY-40354A Purity: 99.92%
Data Sheet SDS Handling Instructions

Tofacitinib citrate inhibits JAK3 with IC50 of 1 nM while inhibiting JAK2, JAK1, Rock-II and Lck with IC50 values of 20 nM, 112 nM, 3,400 nM and 3,870 nM, respectively.

For research use only. We do not sell to patients.
Tofacitinib citrate Chemical Structure

Tofacitinib citrate Chemical Structure

CAS No. : 540737-29-9

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Other Forms of Tofacitinib citrate:

  • Biological Activity

  • Protocol

  • Technical Information

  • Purity & Documentation

  • References

Description

Tofacitinib citrate inhibits JAK3 with IC50 of 1 nM while inhibiting JAK2, JAK1, Rock-II and Lck with IC50 values of 20 nM, 112 nM, 3,400 nM and 3,870 nM, respectively.

IC50 & Target

IC50: 1 nM (JAK3), 20 nM (JAK2), 112 nM (JAK1)[1]

In Vitro

Tofacitinib (CP-690550) citrate binds potentially at JAK3 and JAK2 as 2.2 nM and 5 nM (Kd). The report includes additional binding for Tofacitinib at Camk1 (Kd of 5,000 nM), DCamkL3 (Kd of 4.5 nM), Mst2 (Kd of 4,300 nM), Pkn1 (Kd of 200 nM), Rps6ka2 (Kin.Dom.2-C-terminal) (Kd of 1,400 nM), Rps6ka6 (Kin.Dom.2-C-terminal) (Kd of 1,200 nM), Snark (Kd of 420 nM), Tnk1 (Kd of 640 nM) and Tyk2 (Kd of 620 nM)[1].

In Vivo

Animals that are treated with Tofacitinib show a significantly lower production of anti-drug antibodies (ADAs) compare with PEG-treated control mice (for five weeks after initial immunization, p<0.01, n=8). Moreover ADAs become detectable earliest on day 28. A difference of 1000- to 200-fold in titers to SS1P is apparent from days 21 through 35, respectively. Compare to SS1P, mice injected with keyhole limpet hemocyanin (KLH) generate a more rapid antibody response. Yet, the administration of Tofacitinib reduces anti-KLH titers compare to controls (p<0.05 on day 21, p<0.01 on day 28, respectively, n=5). Reductions in titers ranged from 5000- to 250-fold from days 21 through 28, respectively[2]. Expression of the pro-inflammatory cytokne-cytokine Interferon-gamma (IFNγ) is upregulated in the dorsal horn after peripheral nerve injury, and intrathecal IFNγ administration induces mechanical allodynia in rats. Adding the Janus activated kinase inhibitor Tofacitinib to the pipette solution does not affect the IFNγ-induced facilitation of NMDA-induced currents[3].

Clinical Trial
NCT Number Sponsor Condition Start Date Phase
NCT01202240 Pfizer Healthy September 2010 Phase 1
NCT01226680 Pfizer Keratoconjunctivitis Sicca December 2010 Phase 2
NCT01262118 Pfizer Rheumatoid Arthritis May 2011 Phase 1
NCT01164579 Pfizer Rheumatoid Arthritis October 2010 Phase 2
NCT01204112 Pfizer Healthy September 2010 Phase 1
NCT01143805 Pfizer Healthy July 2010 Phase 1
NCT03002649 Johns Hopkins University|Pfizer Dermatomyositis January 2017 Phase 1
NCT02281552 Pfizer Rheumatoid Arthritis November 18, 2014 Phase 3
NCT03011281 Hanyang University Rheumatoid Arthritis November 2016
NCT02299297 Julian M. Mackay-Wiggan|Locks of Love|Columbia University Alopecia Areata January 2015 Phase 2
NCT02592434 Pfizer Juvenile Idiopathic Arthritis June 10, 2016 Phase 3
NCT02566967 Norman B. Gaylis, MD|Arthritis & Rheumatic Disease Specialties Research Rheumatoid Arthritis May 2015 Phase 3
NCT02812342 Yale University Alopecia Areata|Alopecia Totalis|Alopecia Universalis September 2016 Phase 2
NCT02535689 National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)|National Institutes of Health Clinical Center (CC) Systemic Lupus Erythematosus August 25, 2015 Phase 1
NCT03159936 Tufts Medical Center|Pfizer Discoid Lupus Erythematosus|Systemic Lupus Erythematosus April 3, 2017 Early Phase 1
NCT02487433 Pfizer Healthy June 2015 Phase 1
NCT02084875 Pfizer Healthy April 2014 Phase 1
NCT01500551 Pfizer Juvenile Idiopathic Arthritis March 18, 2013 Phase 3
NCT02321930 University of California, Los Angeles Rheumatoid Arthritis January 2016 Phase 4
NCT01731327 Pfizer Healthy November 2012 Phase 1
NCT02147587 Pfizer Rheumatoid Arthritis June 2014 Phase 2
NCT01976364 Pfizer Arthritis, Psoriatic February 17, 2014 Phase 3
NCT01499004 Pfizer Healthy November 2011 Phase 1
NCT01599377 Pfizer Healthy May 2012 Phase 1
NCT01932372 Pfizer Rheumatoid Arthritis July 26, 2013
NCT02187055 Pfizer Rhematoid Arthritis August 2014 Phase 4
NCT02001181 Pfizer Dermatitis, Atopic December 2013 Phase 2
NCT01786668 Pfizer Ankylosing Spondylitis April 2013 Phase 2
NCT03000439 Pfizer Arthritis Juvenile Idiopathic August 4, 2017 Phase 3
NCT01882439 Pfizer Psoriatic Arthritis August 2013 Phase 3
NCT01831466 Pfizer Psoriasis Vulgaris|Psoriasis May 2013 Phase 2
NCT02312882 Stanford University Alopecia Areata|Alopecia Totalis|Alopecia Universalis December 2014
NCT02197455 Yale University Alopecia Areata (AA)|Alopecia Totalis (AT)|Alopecia Universalis (AU) July 2014 Phase 2
NCT02092467 Pfizer Arthritis, Rheumatoid March 14, 2014 Phase 4
NCT01877668 Pfizer Psoriatic Arthritis January 20, 2014 Phase 3
NCT03112148 Pfizer Healthy September 2017 Phase 1
NCT01375127 Pfizer Kidney Transplantation August 2011
NCT01465763 Pfizer Ulcerative Colitis April 2012 Phase 3
NCT01458951 Pfizer Ulcerative Colitis June 2012 Phase 3
NCT02996500 Pfizer Rheumatoid Arthritis November 10, 2016 Phase 2
NCT03103412 Theravance Biopharma R & D, Inc. Active Mild Ulcerative Colitis, Active Moderate Ulcerative Colitis, Healthy Subjects May 4, 2017 Phase 1
NCT01745055 Pfizer Rheumatoid Arthritis April 2005 Phase 1
NCT01741493 AbbVie (prior sponsor, Abbott)|AbbVie Rheumatoid Arthritis November 2012 Phase 1
NCT02193815 Pfizer Psoriasis Vulgaris September 2014 Phase 1
NCT01710046 Pfizer Plaque Psoriasis March 2013 Phase 2
NCT01736696 Pfizer Psoriasis|Immunomodulation November 2002 Phase 1
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References
Preparing Stock Solutions
Concentration Volume (DMSO) Mass 1 mg 5 mg 10 mg
1 mM 1.9822 mL 9.9110 mL 19.8220 mL
5 mM 0.3964 mL 1.9822 mL 3.9644 mL
10 mM 0.1982 mL 0.9911 mL 1.9822 mL
Kinase Assay
[1]

Kinase activity is recorded via a competition binding assay of selected kinases that are fused to a proprietary tag. Measurements of the amount of kinase binds to an immobilized, active-site directed ligand in the presence and absence of the test compound (e.g., Tofacitinib) provide a % of DMSO control for binding of ligand. Activities between 0 and 10 are selected for Kd determinations. Dendrogram representations are generated by an in-house visualization tool designated PhyloChem[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Cell Assay
[1]

Tofacitinib is solubilized in DMSO and stored, and then diluted with appropriate media before use[1].

Human CD4+ positive cells are enriched from peripheral blood mononuclear cells obtained from a healthy donor by magnetic separation (CD4+ MACS beads). CD4+ cells are activated for 3 days with plate bound anti-CD3 and anti CD28 antibodies (5 ug/mL each), and then expanded for another 4 days in the presence of IL-2 (50 U/mL). Cells are rested overnight in 1% RPMI, and pre-incubated with Tofacitinib or DMSO control for 1 hour at indicated concentrations (5 nM, 50 nM, 500 nM; DMSO concentration is equal in all preparations) and then activated with IL-2 (1000 u/mL) or IL-12 (100 ng/mL) for 15 minutes. Cells (10×106/condition) are lysed in 1% Triton-x lysis buffer and equal amounts of cell lysate are run in NuPage Bis-Tris gel (4-12% gradient). Proteins are transferred onto nitrocellulose membrane. Detection is done with indicated antibodies using Odyssey western blotting system[1]. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Administration
[2][3]

Tofacitinib is resuspended at 100 mg/mL in PEG 300 (Mice)[2].
Tofacitinib citrate is first dissolved in 5% DMSO as 1,000 × stock solutions and diluted to the final concentration before use (Rat)[3].

Mice[2]
Female BALB/c mice (6-8 weeks old) are used. Mice receive Tofacitinib in PEG300 (100 mg/mL) or vehicle alone (PEG300) by osmotic pump infusion (Alzet Model 2004, 0.25 μL/hour, 28 days). Four days prior to immunization, mice are anesthetized and their dorsal surface is shaved. A one cm incision is made on the back to create a subcutaneous pocket and insert the pump. The incision site is closed with wound clips. Mice are injected weekly (i.p.) with SS1P recombinant immunotoxin (RIT; 5 μg/mouse) beginning on day 0; control mice received injections of saline alone. Every week before SS1P or vehicle immunization, ~50 μL of blood is drawn to obtain serum samples. Sera are stored at −80°C until analyzed.
Rat[3]
Five to six-week-old male Sprague Dawley rats (180-210 g) are used. The drugs used in this study are IFNγ; IFNγ antagonist; monocyte chemoattractant protein 1 (MCP-1); and, AMPA, NMDA, minocycline hydrochloride, Teijin compound 1 hydrochloride, GDP-β-S, and Tofacitinib citrate. IFNγ antagonist, MCP-1, AMPA, NMDA, and minocycline hydrochloride are dissolved in distilled water as 1,000 × stock solutions, and Teijin compound 1 hydrochloride and Tofacitinib citrate are first dissolved in 5% DMSO as 1,000 × stock solutions. The 1,000 × stock solutions of IFNγ are prepared in distilled water containing 1% bovine serum albumin (BSA). All perfusion drugs are stored at −20°C and diluted to the final concentration in Krebs solution just before use, and then are perfused via a three-way stopcock without any change in the rate or temperature. The time necessary for the solution to flow from the stopcock to the spinal cord section surface is about 1 min. GDP-β-S and Tofacitinib citrate are added to the pipette solution. The tubing of our perfusion system is coated with AquaSil siliconizing fluid to reduce the loss of IFNγ through nonspecific interactions. MCE has not independently confirmed the accuracy of these methods. They are for reference only.

References
Molecular Weight

504.49

Formula

C₂₂H₂₈N₆O₈

CAS No.

540737-29-9

Storage
Powder -20°C 3 years
  4°C 2 years
In solvent -80°C 6 months
  -20°C 1 month
Shipping

Room temperature in continental US; may vary elsewhere

Solvent & Solubility

DMSO: ≥ 122.5 mg/mL

* "<1 mg/mL" means slightly soluble or insoluble. "≥" means soluble, but saturation unknown.

Purity: 99.92%

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Tofacitinib citrate
Cat. No.:
HY-40354A
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