Tofacitinib (CP-690550) Citrate

Modify Date: 2024-01-02 15:50:41

Tofacitinib (CP-690550) Citrate structure	Common Name	Tofacitinib (CP-690550) Citrate
	CAS Number	540737-29-9	Molecular Weight	504.493
	Density	N/A	Boiling Point	N/A
	Molecular Formula	C₂₂H₂₈N₆O₈	Melting Point	N/A
	MSDS	Chinese USA	Flash Point	N/A

Use of Tofacitinib (CP-690550) Citrate

Tofacitinib citrate is a JAK1/2/3 inhibitor with IC50s of 1, 20, and 112 nM, respectively.

Name	tofacitinib citrate
Synonym	More Synonyms

Description	Tofacitinib citrate is a JAK1/2/3 inhibitor with IC50s of 1, 20, and 112 nM, respectively.
Related Catalog	Signaling Pathways >> Epigenetics >> JAK Signaling Pathways >> JAK/STAT Signaling >> JAK Signaling Pathways >> Stem Cell/Wnt >> JAK Research Areas >> Inflammation/Immunology
Target	JAK3:1 nM (IC50) JAK2:20 nM (IC50) JAK1:112 nM (IC50) Rock-II:3400 nM (IC50) Lck:3870 nM (IC50)
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]. K562, KCL22, and THP-1 cells are exposed to different doses of Imatinib (IMA) or JAK inhibitors for 72 h to quantify the effects of tyrosine kinase inhibitor (TKI) activity. Cell growth inhibition is then evaluated using the MTT assay. The proliferation of K562 and KCL22 cells, but not THP-1 cells, is inhibited by IMA in a concentration-dependent manner. The IC50 value of IMA is 0.28 µM for K562 and 0.17 µM for KCL22. Although treatment with Tofacitinib (TOF) or Ruxolitinib (RUX) alone does not suppress cell proliferation, both Tofacitinib and Ruxolitinib make the K562 and KCL22 more sensitive to IMA[4].
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]. Based on previous dose-response studies, a daily dose of Tofacitinib of 6.2 mg/kg is selected to provide 80% inhibition of hind paw volume and plasma exposure capable of suppressing the JAK1 and JAK3 signaling pathways for >4 hours[3].
Kinase Assay	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].
Cell Assay	Cell survival assay is performed using MTT. Briefly, K562, KCL22, and THP-1 cells (1×105 cells/well) are plated onto 96-well microplates and treated with or without IMA (0.06-1.0 μM) and/or Tofacitinib (10-1,000 nM) or RUX (10-1,000 nM) for 72 h at 37°C in a humidified 5% (v/v) CO2 atmosphere. The medium (200 µL) is then incubated with 10 µL of 5 mg/ml MTT solution for 4 h at 37°C. After being centrifuged at 352 g for 5 min, the culture medium is removed, and 100 µL of DMSO are added to each well to dissolve the formazan. Absorbance is measured at 570 nm using a microplate reader. The results are expressed as percentages[4].
Animal Admin	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 (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. Rats[3] Adjuvant-induced arthritis (AIA) is induced in female Lewis rats. Rats are randomized according to hind paw volume and assigned to Tofacitinib or vehicle treatment regimens. Groups of 7-8 rats per treatment group, and normal naive rats (n=4 per group), are euthanized either 4 hours, 4 days, or 7 days after beginning treatment (days 16, 20, and 23 after immunization, respectively). Once-daily oral administration of vehicle or Tofacitinib (6.2 mg/kg) is initiated on day 16 following immunization and continued through day 23. Paw volumes are reassessed 4 and 7 days after the beginning of treatment (days 20 and 23 after immunization, respectively). For micro-computed tomography (micro-CT) imaging, as well as tartrate-resistant acid phosphatase (TRAP) staining in paw tissue, AIA is induced in a separate cohort of Lewis rats.
References	[1]. Jiang JK, et al. Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). J Med Chem. 2008 Dec 25;51(24):8012-8. [2]. Onda M, et al. Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts. J Immunol. 2014 Jul 1;193(1):48-55. [3]. LaBranche TP, et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 2012 Nov;64(11):3531-42. [4]. Yagi K, et al. Pharmacological inhibition of JAK3 enhances the antitumor activity of imatinib in human chronic myeloid leukemia. Eur J Pharmacol. 2018 Apr 15;825:28-33.

Molecular Formula	C₂₂H₂₈N₆O₈
Molecular Weight	504.493
Exact Mass	504.196869
PSA	221.04000
LogP	0.23418
Appearance of Characters	white to beige
Storage condition	room temp
Water Solubility	DMSO: soluble5mg/mL (clear solution; warmed)

Tofacitinib (CP-690550) Citrate MSDS(Chinese)

RIDADR	NONH for all modes of transport

Impact of irradiation and immunosuppressive agents on immune system homeostasis in rhesus macaques.

Clin. Exp. Immunol. 181 , 491-510, (2015)

In this study we examined the effects of non-myeloablative total body irradiation (TBI) in combination with immunosuppressive chemotherapy on immune homeostasis in rhesus macaques. Our results show th...

Tofacitinib citrate

Xeljanz

Tasocitinib citrate

3-{(3R,4R)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1-piperidinyl}-3-oxopropanenitrile 2-hydroxy-1,2,3-propanetricarboxylate (1:1)

1-Piperidinepropanenitrile, 4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-, (3R,4R)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) (salt)

CP690550 citrate

3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile 2-hydroxypropane-1,2,3-tricarboxylate

Tofacitinibcitrate

2-hydroxypropane-1,2,3-tricarboxylic acid,3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile