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TASOCITINIB: THE REVOLUTION IN ARTHRITIS MANAGEMENT

Introduction: Inhibition of the JAK pathway

The protein kinases are a super family of protein that govern the control of cellular growth, creation of vascular structure and many other processes the control the way in which cells and tissue regenerate. In is estimated that 30% of all cellular regulation is governed by protein kinases. Protein kinases are subdivided into 7 different classifications of which one is the tyrosine kinases. These kinases operate by phosphorylation of a tyrosine amino acid residue transferring a signal down a cascade of protein to regulate cellular processes. A further subdivision of the tyrosine kinases can be made into receptor based kinases and non receptor based kinases. The Janus kinases (JAK) are a sub family of the receptor based tyrosine kinases. Signals from the JAK regulate the cytokines, the GM-CSF family and the GP130 receptor family. JAK kinases exist in the 4 distinct isoforms with twinned phosphorylation domains. Inhibitors of the JAK kinases have been demonstrated to have a positive effect on cancerous cells both in vivo and in vitro. Tasocitinib is a small molecule TK inhibitor that specifically targets the JAK3 kinase; it has a limit inhibitory affinity for JAK1, 2 and 4 [1]. Tasocitinib was designed to target JAK3 in response to the observation that primary immunodeficiency in the JAK3 kinase results in SCID (severe combined immunodeficiency). [2] SCID is implicated in infections in early new born baby’s, arthritis [3], inflammatory bowel disease [4] and transplant rejection [5] to name but a few. Tasocitinib has sufficient anti tumor activity to be carried into clinical investigations.

Tasocitinib: Properties and Availability

Tasocitinib is a Pfizer Plc chemical name and the formulation name for this molecule is Tofacitinib, although originally it was researched with the drug code CP-690550. Tasocitinib structure is based on mono substituted purine molecule. The Tasocitinib IC50 for JAK3 is 0.2 µM as referenced to PV progenitor cells. Tasocitinib solubility is similar to all molecules of this nature in that it is very nearly insoluble in water. For research purposes Tasocitinib can be dissolved in both DMSO and ethanol to a maximum concentration of 100 mg/ml. Tasocitinib stability for research storage has been determined for the free base, with storage at -20oC or lower the expiration date can be set to 2 years. To buy Tasocitinib free base there are several reliable Tasocitinib suppliers with good purity product, although Tasocitinib price range from $62 up to $250 for a 10 mg vial.

PRECLINICAL ACHIEVEMENTS OF TASOCITINIB: 

In natural killer cells (NK) of a primate model the transmembrane protein CD69 was observed to decrease after Tasocitinib administration indicate Il5 inhibition [6] whereas in a separate investigations the CD8 T-cell and the CD4 cell where significantly reduced along with the NK cells [7] . These effects indicated a strong immunosuppression ability for Tasocitinib prompting phase 1 trials in organ transplants to reduce organ rejections [8]. As well as immunosuppression abilities Tasocitinib has been reported as having anti-inflammatory properties indicating possible uses in asthma, rhinitis and stroke recovery [9;10]. Another inflammatory condition is Rheumatoid arthritis and Tasocitinib is recorded as effective in suppressing this disease so much so that phase 1 Tasocitinib clinical trials are currently in progress [11-13]. Other disease targets of Tasocitinib are psoriasis, hematological malignancies, Adult T-cell leukemia and brain ischemia [10;14-16]. These trials all demonstrated Tasocitinib’s potential in the clinical setting.

Tasocitinib: Clinical status

Tasocitinib psoriasis has been successfully treated with 75 – 90% improvement seen in symptoms in a phase 2 trial [16;17] Phase II trials have been conducted with Tasocitinib in relation to rheumatoid arthritis where highly significant efficacy was seen, although the safety profile for the drug was borderline [18-21] In addition Tasocitinib has continuously demonstrates its effectiveness in the immunosuppression of transplant rejection both in heart and kidney [5;22;23]. Phase 3 trials (NCT00413699) are ongoing for rheumatoid arthritis and psoriasis with the results expected in the next few years.

References

    1.    Tasocitinib. Drugs R D 2010; 10(4):271-284.

    2.    Vijayakrishnan L, Venkataramanan R et al. Treating inflammation with the Janus kinase inhibitor CP-690,550. Trends Pharmacol Sci 2011; 32(1):25-34.

    3.    Riese RJ, Krishnaswami S et al. Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract Res Clin Rheumatol 2010; 24(4):513-526.

    4.    West K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs 2009; 10(5):491-504.

    5.    Wojciechowski D, Vincenti F. Targeting JAK3 in kidney transplantation: current status and future options. Curr Opin Organ Transplant 2011; 16(6):614-619.

    6.    Conklyn M, Andresen C et al. The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing. J Leukoc Biol 2004; 76(6):1248-1255.

    7.    Borie DC, Changelian PS et al. Immunosuppression by the JAK3 inhibitor CP-690,550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates. Transplantation 2005; 79(7):791-801.

    8.    van GE, Weimar W et al. Phase 1 dose-escalation study of CP-690 550 in stable renal allograft recipients: preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics. Am J Transplant 2008; 8(8):1711-1718.

    9.    Kudlacz E, Conklyn M et al. The JAK-3 inhibitor CP-690550 is a potent anti-inflammatory agent in a murine model of pulmonary eosinophilia. Eur J Pharmacol 2008; 582(1-3):154-161.

  10.    Konoeda F, Shichita T et al. Therapeutic effect of IL-12/23 and their signaling pathway blockade on brain ischemia model. Biochem Biophys Res Commun 2010; 402(3):500-506.

  11.    Kremer JM, Bloom BJ et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009; 60(7):1895-1905.

  12.    West K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr Opin Investig Drugs 2009; 10(5):491-504.

  13.    Milici AJ, Kudlacz EM et al. Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arthritis Res Ther 2008; 10(1):R14.

  14.    Ju W, Zhang M et al. CP-690,550, a therapeutic agent, inhibits cytokine-mediated Jak3 activation and proliferation of T cells from patients with ATL and HAM/TSP. Blood 2011; 117(6):1938-1946.

  15.    Cornejo MG, Boggon TJ et al. JAK3: a two-faced player in hematological disorders. Int J Biochem Cell Biol 2009; 41(12):2376-2379.

  16.    Boy MG, Wang C et al. Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol 2009; 129(9):2299-2302.

  17.    Tasocitinib. Drugs R D 2010; 10(4):271-284.

  18.    Kremer JM, Cohen S et al. A Phase 2B dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate alone. Arthritis Rheum 2011.

  19.    Fleischmann R, Cutolo M et al. Phase 2B dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to DMARDs. Arthritis Rheum 2011.

  20.    Tanaka Y, Suzuki M et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken ) 2011; 63(8):1150-1158.

  21.    Riese RJ, Krishnaswami S et al. Inhibition of JAK kinases in patients with rheumatoid arthritis: scientific rationale and clinical outcomes. Best Pract Res Clin Rheumatol 2010; 24(4):513-526.

  22.    Djamali A, Pietrangeli CE et al. Potential of emerging immunosuppressive strategies to improve the posttransplant cardiovascular risk profile. Kidney Int Suppl 2010;(118):S15-S21.

  23.    Cooper JE, Wiseman AC. Novel immunosuppressive agents in kidney transplantation. Clin Nephrol 2010; 73(5):333-343.

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S5001 Tofacitinib (CP-690550) Citrate Tofacitinib citrate (CP-690550, Tasocitinib) is a novel inhibitor of JAK with IC50 of 1 nM, 20 nM and 112 nM against JAK3, JAK2, and JAK1, respectively. Tofacitinib citrate has anti-infection activity. (174) (4)

Related Targets

JAK