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CP-690550: THE CURE FOR ARTHRITIS

by Selleckchem | Mar 20 2012

Introduction: JAK and its role in signaling pathways

The protein kinase family plays an essential role in the government of the growth or death properties of mammalian tissues. These proteins form an interrelated, redundant system that is capable of selectively initiating the growth of certain cell types in response to the needs of the host system. To do this the protein kinase super family is subdivided into a series of related protein kinases which make up a signaling pathway, traveling from the extracellular matrix into the cell nucleus. The Janus kinase pathway is one which is activated in response to the action of cytokines on the cytokine transmembrane receptors. Since these receptors have no kinase ability themselves they are total dependant on the Janus kinases (JAK) for activity [1].

Uniquely among the protein kinase this family of kinases have two independent binding domains, one for phosphorylation of subject proteins for signal transference and one to regulate its own phosphorylation ability, hence the name JANUS [2]. JAK proteins exist in four different isoforms known more formally as JAK- (1-2or 3) as well as tyrosine kinase 2 (TYK2). JAK’s pass their signal into the nucleus via the STAT proteins and ultimately effect the transcription of various genes. While JAK1 and 2 are known to trigger signaling in the interferon (gamma) pathway, JAK 3 has been linked to immuno –response factors such as cell survival and lymphocyte differentiation. It has been observed in certain metabolic disorders that aberrant JAK 3 signaling can lead to a condition called severe combined immunodeficiency or SCID. This is related to diseases the formation of T- or B- cell is of a critical importance such as lung cancer, hematological disorders and arthritis [3].

Inhibition of this pathway via the JAK 3 isoform would, therefore, be considered and effective treatment direction [4], Signals from aberrant cytokines such as the il-2 family would be halted at an early stage in the pathway, prior to the triggering of nucleus functions [5-9]. However, clinically Janus kinase inhibitors have demonstrated variable activity, toxicity can be high and responses low. CP-690550 is a relatively new molecule introduced as a selective inhibitor of the JAK3 isoform with significantly less activity for JAK 1 and JAK 2 [10].

CP690550: Properties and availability

The CP-690550 JAK inhibitor is the research code name for the market drug Tofacitinib which is also another name for the molecule Tasocitinib. Under development by Pfizer, Plc this molecule has changed names twice which can be confusing. Currently it is being research under the name Tasocitinib but literature reports it mostly as Tofacitinib. The CP-690550 solubility is relatively good in both DMSO and ethanolic solutions reaching saturation at approximately 100 mg/ml. However, similar to nearly all tyrosine kinase inhibitors this molecule is virtually insoluble at physiological pH’s in water, this represents a significant challenge to the development of an effective oral drug formulation. The CP690550 structure is a based on a nucleoside core (purine) with a single substituted side chain while CP690550 stability has been determined to be relatively good with a recommended expiration date of 2 years if stored at -20°C. In terms of the CP-690550 IC50 towards JAK3, values of 200 nM have been determined [11]. Cp690550 is freely available with researchers able to buy CP-690550 from several different CP-690550 suppliers although the CP-690550 price can range from $62 - $250 for only 10 mgs of product.

Preclinical Investigations

The lack of JAK 2 in a primate model has demonstrated that the natural killer cells (NK) are ineffective [12;13], this has been linked to the inhibition of interleukin 5, a cytokine which signals through the Janus kinase family. Surprisingly treatment with CP690550 also demonstrated abilities to decease iL-5 signaling in addition to decreasing T-cell formation [12;14]. In arthritis CP690550 has shown prolific effects in vitro cell cultures that have also been transferred to animal models [15]. In addition effects have been observed in asthma, stroke recovery and hay fever which all can be related to anti-inflammatory functions for this molecule [16].

Clinical Status

CP-690550 clinical trials were successfully initiated in arthritis with highly effective results being reported [17] and was also seen to make significant differences for psoriasis patients at phase II level [18;19]. As an immunosuppressant, CP690550 has been successfully trialed in kidney transplant cases with such effective results it confirms that this molecule represents a clear clinical improvement [20;21]. Various clinical trials are being initiated at various levels in psoriasis, arthritis and as an immunosuppressant.

References

1. Caraglia M, Vitale G et al. Alpha-interferon and its effects on signalling pathways within cells. Curr Protein Pept Sci 2004; 5(6):475-485.

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

3. Seavey MM, Dobrzanski P. The many faces of Janus kinase. Biochem Pharmacol 2011.

4. Borie DC, Si MS et al. JAK3 inhibition as a new concept for immune suppression. Curr Opin Investig Drugs 2003; 4(11):1297-1303.

5. Cooney RN. Suppressors of cytokine signaling (SOCS): inhibitors of the JAK/STAT pathway. Shock 2002; 17(2):83-90.

6. Alexander WS, Starr R et al. Suppressors of cytokine signaling (SOCS): negative regulators of signal transduction. J Leukoc Biol 1999; 66(4):588-592.

7. Diamond P, Doran P et al. Suppressors of cytokine signalling (SOCS): putative modulators of cytokine bioactivity in health and disease. J Nephrol 2000; 13(1):9-14.

8. Greenhalgh CJ, Alexander WS. Suppressors of cytokine signalling and regulation of growth hormone action. Growth Horm IGF Res 2004; 14(3):200-206.

9. Larsen L, Ropke C. Suppressors of cytokine signalling: SOCS. APMIS 2002; 110(12):833-844.

10. Kudlacz E, Perry B et al. The novel JAK-3 inhibitor CP-690550 is a potent immunosuppressive agent in various murine models. Am J Transplant 2004; 4(1):51-57.

11. Changelian PS, Moshinsky D et al. The specificity of JAK3 kinase inhibitors. Blood 2008; 111(4):2155-2157.

12. Park HB, Oh K et al. CP-690550, a Janus kinase inhibitor, suppresses CD4+ T-cell-mediated acute graft-versus-host disease by inhibiting the interferon-gamma pathway. Transplantation 2010; 90(8):825-835.

13. Borie DC, Larson MJ et al. Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates. Transplantation 2005; 80(12):1756-1764.

14. Maeshima K, Yamaoka K et al. A JAK inhibitor tofacitinib regulates synovitis through inhibition of IFN-gamma and IL-17 production by human CD4(+) T cells. Arthritis Rheum 2011.

15. Manshouri T, Quintas-Cardama A et al. The JAK kinase inhibitor CP-690,550 suppresses the growth of human polycythemia vera cells carrying the JAK2V617F mutation. Cancer Sci 2008; 99(6):1265-1273.

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

17. 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.

18. 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.

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

20. Paniagua R, Si MS et al. Effects of JAK3 inhibition with CP-690,550 on immune cell populations and their functions in nonhuman primate recipients of kidney allografts. Transplantation 2005; 80(9):1283-1292.

21. van Gurp EA, Schoordijk-Verschoor W et al. The effect of the JAK inhibitor CP-690,550 on peripheral immune parameters in stable kidney allograft patients. Transplantation 2009; 87(1):79-86.