Tofacitinib
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MedKoo CAT#: 200811

CAS#: 477600-75-2 (free base)

Description: Tofacitinib, also known as tasocitinib, CP-690550, is a Janus kinase (JAK) inhibitor. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively.


Chemical Structure

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Tofacitinib
CAS# 477600-75-2 (free base)

Theoretical Analysis

MedKoo Cat#: 200811
Name: Tofacitinib
CAS#: 477600-75-2 (free base)
Chemical Formula: C16H20N6O
Exact Mass: 312.16986
Molecular Weight: 312.37
Elemental Analysis: C, 61.52; H, 6.45; N, 26.90; O, 5.12

Price and Availability

Size Price Availability Quantity
100.0mg USD 90.0 Ready to ship
200.0mg USD 150.0 Ready to ship
500.0mg USD 250.0 Ready to ship
1.0g USD 450.0 Ready to ship
2.0g USD 850.0 Ready to ship
5.0g USD 1750.0 Ready to ship
10.0g USD 2850.0 Ready to ship
20.0g USD 4250.0 Ready to ship
100.0g USD 8950.0 2 Weeks
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Related CAS #: 540737-29-9 (citrate)   477600-75-2 (free base)   1443435-54-8 (oxalate)   1443435-50-4 (tartrate)   1803005-18-6 (HCl)   1803005-19-7 (HBr)   2052885-67-1 (maleate)    

Synonym: Tofacitinib free base; CP690550; CP-690550; CP 690550; Tofacitinib. Trade name Xeljanz

IUPAC/Chemical Name: 3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile

InChi Key: UJLAWZDWDVHWOW-YPMHNXCESA-N

InChi Code: InChI=1S/C16H20N6O/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1

SMILES Code: N#CCC(N1C[C@H](N(C)C2=C3C(NC=C3)=NC=N2)[C@H](C)CC1)=O

Appearance: White to off-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 (15mg/ mL)

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: Tofacitinib is an orally available JAK3/2/1 inhibitor with IC50s of 1, 20, and 112 nM, respectively.
In vitro activity: Initially, this study tested the cell viability of keratinocytes, synoviocytes, and T cells in the presence of tofacitinib in a range of concentrations (Supplemental Fig. 1). After confirming that cell viability is not affected by tofacitinib, this study subjected RNA from keratinocytes treated with 600 nM tofacitinib or untreated to DNA MicroArray. To display a broad overview of differentially regulated genes, a heatmap is shown in Fig. 1a. The presence of tofacitinib quite drastically changes the overall gene expression pattern. Blue depicts upregulated genes, while red shows downregulated genes. A number of antiviral genes are downregulated (such as MX1, MX2, OAS1), while antimicrobial genes such as S100A8 and S100A9 (lower end of heat map) seem to only be minimally affected by JAK inhibition (Fig. 1a). Reference: Arthritis Res Ther. 2021; 23: 144. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138978/
In vivo activity: Here this study used mouse models to ask if tofacitinib is able to block pathology induced by cytolytic CD8 T cells while sparing protective Th1 responses. Collectively, these series of experiments suggest tofacitinib is an inhibitor that should be considered for the treatment of CL (cutaneous leishmaniasis). The use of host-directed therapies that block inflammatory responses might be considered problematic in infectious diseases, since it is possible that protective responses might simultaneously be dampened. Since Leishmania killing requires the development of a Th1 response, blocking either IL-12 or IFN-γ might lead to uncontrolled parasite growth. However, this study found that tofacitinib had a mild impact on IFN-γ production by CD4 T cells stimulated with IL-12 and IL-18, and in vivo tofacitinib treatment had no impact on the production of IFN-γ during infection. Furthermore, in CL this study has identified an immunopathologic response that can be blocked without affecting parasite control. Thus, tofacitinib inhibited CD8 T cell mediated pathology, while Th1 responses remained intact. Thus, tofacitinib, used in combination with anti-parasitic drugs, would be a successful and to this study’s knowledge a previously unreported strategy for the treatment of CL. Reference: J Invest Dermatol. 2021 Mar; 141(3): 575–585. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855313/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 72.15 230.98
Ethanol 2.5 8.0
Water 0.15 0.48

Preparing Stock Solutions

The following data is based on the product molecular weight 312.37 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. Hawerkamp HC, Domdey A, Radau L, Sewerin P, Oláh P, Homey B, Meller S. Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation. Arthritis Res Ther. 2021 May 21;23(1):144. doi: 10.1186/s13075-021-02509-8. PMID: 34020693; PMCID: PMC8138978. 2. Wong J, Wall M, Corboy GP, Taubenheim N, Gregory GP, Opat S, Shortt J. Failure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations. Cold Spring Harb Mol Case Stud. 2020 Aug 25;6(4):a004994. doi: 10.1101/mcs.a004994. PMID: 32843425; PMCID: PMC7476415. 3. Novais FO, Nguyen BT, Scott P. Granzyme B Inhibition by Tofacitinib Blocks the Pathology Induced by CD8 T Cells in Cutaneous Leishmaniasis. J Invest Dermatol. 2021 Mar;141(3):575-585. doi: 10.1016/j.jid.2020.07.011. Epub 2020 Jul 30. PMID: 32738245; PMCID: PMC7855313. 4. Pérez-Baos S, Gratal P, Barrasa JI, Lamuedra A, Sánchez-Pernaute O, Herrero-Beaumont G, Largo R. Inhibition of pSTAT1 by tofacitinib accounts for the early improvement of experimental chronic synovitis. J Inflamm (Lond). 2019 Jan 29;16:2. doi: 10.1186/s12950-019-0206-2. PMID: 30728752; PMCID: PMC6352431.
In vitro protocol: 1. Hawerkamp HC, Domdey A, Radau L, Sewerin P, Oláh P, Homey B, Meller S. Tofacitinib downregulates antiviral immune defence in keratinocytes and reduces T cell activation. Arthritis Res Ther. 2021 May 21;23(1):144. doi: 10.1186/s13075-021-02509-8. PMID: 34020693; PMCID: PMC8138978. 2. Wong J, Wall M, Corboy GP, Taubenheim N, Gregory GP, Opat S, Shortt J. Failure of tofacitinib to achieve an objective response in a DDX3X-MLLT10 T-lymphoblastic leukemia with activating JAK3 mutations. Cold Spring Harb Mol Case Stud. 2020 Aug 25;6(4):a004994. doi: 10.1101/mcs.a004994. PMID: 32843425; PMCID: PMC7476415.
In vivo protocol: 1. Novais FO, Nguyen BT, Scott P. Granzyme B Inhibition by Tofacitinib Blocks the Pathology Induced by CD8 T Cells in Cutaneous Leishmaniasis. J Invest Dermatol. 2021 Mar;141(3):575-585. doi: 10.1016/j.jid.2020.07.011. Epub 2020 Jul 30. PMID: 32738245; PMCID: PMC7855313. 2. Pérez-Baos S, Gratal P, Barrasa JI, Lamuedra A, Sánchez-Pernaute O, Herrero-Beaumont G, Largo R. Inhibition of pSTAT1 by tofacitinib accounts for the early improvement of experimental chronic synovitis. J Inflamm (Lond). 2019 Jan 29;16:2. doi: 10.1186/s12950-019-0206-2. PMID: 30728752; PMCID: PMC6352431.

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1. Dai Z, Chen J, Chang Y, Christiano AM. Selective inhibition of JAK3 signaling is sufficient to reverse alopecia areata. JCI Insight. 2021 Apr 8;6(7):142205. doi: 10.1172/jci.insight.142205. PMID: 33830087.

1: Barrera MJ, Aguilera S, Castro I, Matus S, Carvajal P, Molina C, González S, Jara D, Hermoso M, González MJ. Tofacitinib counteracts IL-6 overexpression induced by deficient autophagy: implications in Sjögren's syndrome. Rheumatology (Oxford). 2020 Nov 12:keaa670. doi: 10.1093/rheumatology/keaa670. Epub ahead of print. PMID: 33216905.

2: Song GG, Lee YH. Relative efficacy and safety of tofacitinib for treating psoriasis: A Bayesian network meta-analysis of randomized controlled trials. Int J Clin Pharmacol Ther. 2020 Nov 19. doi: 10.5414/CP203831. Epub ahead of print. PMID: 33210996.

3: Sedano R, Jairath V. Tofacitinib Induced Long-term Clinical, Endoscopic, and Histological Remission as a 6th Line Agent in Medically Refractory Ulcerative Colitis. Inflamm Bowel Dis. 2020 Nov 17:izaa296. doi: 10.1093/ibd/izaa296. Epub ahead of print. PMID: 33200783.

4: Li X, Wu X, Elston DM, Zhang J, Zhou C. Hypohidrotic Ectodermal Dysplasia with c.28delG Mutation in Ectodysplasin A Gene and Severe Atopic Dermatitis Treated Successfully with Tofacitinib. Acta Derm Venereol. 2020 Nov 16. doi: 10.2340/00015555-3693. Epub ahead of print. PMID: 33196100.

5: Bae D, Choi Y, Lee J, Ha N, Suh D, Baek J, Park J, Son W. M-134, a novel HDAC6-selective inhibitor, markedly improved arthritic severity in a rodent model of rheumatoid arthritis when combined with tofacitinib. Pharmacol Rep. 2020 Nov 13. doi: 10.1007/s43440-020-00188-x. Epub ahead of print. PMID: 33188511.

6: You H, Xu D, Hou Y, Zhou J, Wang Q, Li M, Zeng X. Tofacitinib as a possible treatment for skin thickening in diffuse cutaneous systemic sclerosis. Rheumatology (Oxford). 2020 Nov 14:keaa613. doi: 10.1093/rheumatology/keaa613. Epub ahead of print. PMID: 33188425.

7: Sleutjes JAM, de Vries AC, van der Woude CJ, Roeters van Lennep JE. Lipid Profiles in Patients With Ulcerative Colitis Receiving Tofacitinib-Implications for Cardiovascular Risk and Patient Management. Inflamm Bowel Dis. 2020 Nov 6:izaa295. doi: 10.1093/ibd/izaa295. Epub ahead of print. PMID: 33155646.

8: Watanabe R, Hashimoto M, Morinobu A. Correspondence on 'The use of tocilizumab and tofacitinib in patients with resolved hepatitis B infection: a case series'. Ann Rheum Dis. 2020 Nov 3:annrheumdis-2020-219270. doi: 10.1136/annrheumdis-2020-219270. Epub ahead of print. PMID: 33144301.

9: Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Schoeman C, Wang L, Chen C, Kwok K, Biswas P, Shapiro A, Madsen A, Wollenhaupt J. Long-term safety of tofacitinib up to 9.5 years: a comprehensive integrated analysis of the rheumatoid arthritis clinical development programme. RMD Open. 2020 Oct;6(3):e001395. doi: 10.1136/rmdopen-2020-001395. PMID: 33127856.

10: Sandborn WJ, Peyrin-Biroulet L, Quirk D, Wang W, Nduaka CI, Mukherjee A, Su C, Sands BE. Efficacy and Safety of Extended Induction with Tofacitinib for the Treatment of Ulcerative Colitis. Clin Gastroenterol Hepatol. 2020 Oct 27:S1542-3565(20)31496-8. doi: 10.1016/j.cgh.2020.10.038. Epub ahead of print. PMID: 33127596.

11: Crespo Cruz A, Del Boz J, Romero Gómez C. Good Response to Tofacitinib in Refractory Amyopathic Dermatomyositis. Actas Dermosifiliogr. 2020 Oct 27:S0001-7310(20)30434-8. English, Spanish. doi: 10.1016/j.ad.2019.07.016. Epub ahead of print. PMID: 33127420.

12: Jia E, Yan G, Xiao M, Geng H, Wei J, Zhang J. Refractory ulcerations associated with livedoid vasculopathy successfully treated with tofacitinib. Dermatol Ther. 2020 Oct 28:e14470. doi: 10.1111/dth.14470. Epub ahead of print. PMID: 33112475.

13: Verstockt B, Pouillon L, Bossuyt P. Tofacitinib and subacute pneumonitis, don't hold your breath. J Crohns Colitis. 2020 Oct 26:jjaa218. doi: 10.1093/ecco-jcc/jjaa218. Epub ahead of print. PMID: 33104197.

14: Jerjen R, Meah N, Trindade de Carvalho L, Wall D, Eisman S, Sinclair R. Treatment of alopecia areata in pre-adolescent children with oral tofacitinib: A retrospective study. Pediatr Dermatol. 2020 Oct 25. doi: 10.1111/pde.14422. Epub ahead of print. PMID: 33099833.

15: Dincer D, Tanacan E, Kose Ozkan C. Efficacy of systemic minoxidil and tofacitinib combination in treatment-resistant alopecia universalis. J Cosmet Dermatol. 2020 Oct 24. doi: 10.1111/jocd.13812. Epub ahead of print. PMID: 33098729.

16: Trigo-Vicente C, Gimeno-Ballester V, López-Del Val A. Cost-effectiveness analysis of infliximab, adalimumab, golimumab, vedolizumab and tofacitinib for moderate to severe ulcerative colitis in Spain. Eur J Hosp Pharm. 2020 Nov;27(6):355-360. doi: 10.1136/ejhpharm-2018-001833. Epub 2019 May 7. PMID: 33097619.

17: Bishu S, Melia J, Sharfman W, Lao CD, Fecher LA, Higgins PD. Efficacy and outcome of Tofacitinib in Immune checkpoint inhibitor colitis. Gastroenterology. 2020 Oct 20:S0016-5085(20)35316-6. doi: 10.1053/j.gastro.2020.10.029. Epub ahead of print. PMID: 33096100.

18: Razmjou AA, Brook J, Elashoff D, Kaeley G, Choi S, Kermani T, Ranganath VK. Ultrasound and multi-biomarker disease activity score for assessing and predicting clinical response to tofacitinib treatment in patients with rheumatoid arthritis. BMC Rheumatol. 2020 Oct 19;4:55. doi: 10.1186/s41927-020-00153-4. PMID: 33089069; PMCID: PMC7569763.

19: Bing SJ, Lyu C, Xu B, Wandu WS, Hinshaw SJ, Furumoto Y, Caspi RR, Gadina M, Gery I. Tofacitinib inhibits the development of experimental autoimmune uveitis and reduces the proportions of Th1 but not of Th17 cells. Mol Vis. 2020 Sep 26;26:641-651. PMID: 33088168; PMCID: PMC7531779.

20: Li B, Li GW, Xue L, Chen YY. Rapid remission of refractory synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome in response to the Janus kinase inhibitor tofacitinib: A case report. World J Clin Cases. 2020 Oct 6;8(19):4527-4534. doi: 10.12998/wjcc.v8.i19.4527. PMID: 33083414; PMCID: PMC7559655.



Additional Information

It is an inhibitor of the enzyme janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription. Recently it has been shown in a murine model of established arthritis that tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.