Janus Kinase 3

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Fatih M. Uckun - One of the best experts on this subject based on the ideXlab platform.

  • prevention of islet allograft rejection in diabetic mice by targeting Janus Kinase 3 with 4 4 hydroxyphenyl amino 6 7 dimethoxyquinazoline janex 1
    Drug Research, 2011
    Co-Authors: Marina Cetkoviccvrlje, Angela L Dragt, Fatih M. Uckun
    Abstract:

    Janus Kinase (JAK) 3-deficient mice were not able to reject allogeneic islet allografts. The JAK3 inhibitor 4-(4’-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline (CAS 202475-60-3, JANEX-1, WHI-P131) prevented the rejection of islet allo-grafts in mice with a normal JAK3 expression status. The combination of JANEX-1 and cyclosporin A (CAS 59865-13-3) was more effective than either agent alone.

  • Janus Kinase 3 inhibitor whi p131 janex 1 prevents graft versus host disease but spares the graft versus leukemia function of the bone marrow allografts in a murine bone marrow transplantation model
    Blood, 2002
    Co-Authors: Fatih M. Uckun, Bertram A Roers, Barbara Waurzyniak, Marina Cetkoviccvrlje
    Abstract:

    The purpose of the present study was to evaluate the effects of graft-versus-host disease (GVHD) prophylaxis with the Janus Kinase 3 (JAK3) inhibitor WHI-P131/JANEX-1 on the graft-versus-leukemic (GVL) function of marrow allografts in mice undergoing bone marrow transplantation (BMT) after being challenged with an otherwise invariably fatal dose of BCL-1 leukemia cells. GVHD prophylaxis using WHI-P131 markedly improved the survival outcome after BMT. The probability of survival at 30 days after BMT was 11% ± 6% for vehicle-treated recipients (median survival time, 25 days) versus 63% ± 12% for recipients treated with WHI-P131 (median survival time, 36 days; P  < .0001). Because WHI-P131 is devoid of antileukemic activity against BCL-1 leukemia cells, this marked improvement in survival outcome was due to reduced incidence of GVHD-associated fatalities combined with sustained GVL function of the allografts in the WHI-P131 group. Notably, adoptive transfer experiments demonstrated that the spleens of WHI-P131–treated allograft recipients contained less than 0.001% BCL-1 cells. Notably, GVHD prophylaxis with WHI-P131 plus methotrexate resulted in 100% survival of mice receiving allotransplants challenged with an otherwise invariably fatal dose of BCL-1 leukemia. Taken together, our results provide strong experimental evidence that GVHD prophylaxis using WHI-P131 does not impair the GVL function of the allografts and consequently contributes to an improved post-BMT survival outcome of the recipient mice.

  • transcription factor stat5a is a substrate of bruton s tyrosine Kinase in b cells
    Journal of Biological Chemistry, 2001
    Co-Authors: Sandeep Mahajan, Alexei Vassilev, Zahide Ozer, Fatih M. Uckun
    Abstract:

    Abstract STAT5A is a molecular regulator of proliferation, differentiation, and apoptosis in lymphohematopoietic cells. Here we show that STAT5A can serve as a functional substrate of Bruton's tyrosine Kinase (BTK). Purified recombinant BTK was capable of directly binding purified recombinant STAT5A with high affinity (K d = 44 nm), as determined by surface plasmon resonance using a BIAcore biosensor system. BTK was also capable of tyrosine-phosphorylating ectopically expressed recombinant STAT5A on Tyr694 both in vitro and in vivo in a Janus Kinase 3-independent fashion. BTK phosphorylated the Y665F, Y668F, and Y682F,Y683F mutants but not the Y694F mutant of STAT5A. STAT5A mutations in the Src homology 2 (SH2) and SH3 domains did not alter the BTK-mediated tyrosine phosphorylation. Recombinant BTK proteins with mutant pleckstrin homology, SH2, or SH3 domains were capable of phosphorylating STAT5A, whereas recombinant BTK proteins with SH1/Kinase domain mutations were not. In pull-down experiments, only full-length BTK and its SH1/Kinase domain (but not the pleckstrin homology, SH2, or SH3 domains) were capable of binding STAT5A. Ectopically expressed BTK Kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr694 mutant) STAT5A enhanced its DNA binding activity. In BTK-competent chicken B cells, anti-IgM-stimulated tyrosine phosphorylation of STAT5 protein was prevented by pretreatment with the BTK inhibitor LFM-A13 but not by pretreatment with the JAK3 inhibitor HI-P131. B cell antigen receptor ligation resulted in enhanced tyrosine phosphorylation of STAT5 in BTK-deficient chicken B cells reconstituted with wild type human BTK but not in BTK-deficient chicken B cells reconstituted with Kinase-inactive mutant BTK. Similarly, anti-IgM stimulation resulted in enhanced tyrosine phosphorylation of STAT5A in BTK-competent B cells from wild type mice but not in BTK-deficient B cells from XID mice. In contrast to B cells from XID mice, B cells from JAK3 knockout mice showed a normal STAT5A phosphorylation response to anti-IgM stimulation. These findings provide unprecedented experimental evidence that BTK plays a nonredundant and pivotal role in B cell antigen receptor-mediated STAT5A activation in B cells.

  • transcription factor stat5a is a substrate of bruton s tyrosine Kinase in b cells
    Journal of Biological Chemistry, 2001
    Co-Authors: Sandeep Mahajan, Alexei Vassilev, Zahide Ozer, Fatih M. Uckun
    Abstract:

    Abstract STAT5A is a molecular regulator of proliferation, differentiation, and apoptosis in lymphohematopoietic cells. Here we show that STAT5A can serve as a functional substrate of Bruton's tyrosine Kinase (BTK). Purified recombinant BTK was capable of directly binding purified recombinant STAT5A with high affinity (K d = 44 nm), as determined by surface plasmon resonance using a BIAcore biosensor system. BTK was also capable of tyrosine-phosphorylating ectopically expressed recombinant STAT5A on Tyr694 both in vitro and in vivo in a Janus Kinase 3-independent fashion. BTK phosphorylated the Y665F, Y668F, and Y682F,Y683F mutants but not the Y694F mutant of STAT5A. STAT5A mutations in the Src homology 2 (SH2) and SH3 domains did not alter the BTK-mediated tyrosine phosphorylation. Recombinant BTK proteins with mutant pleckstrin homology, SH2, or SH3 domains were capable of phosphorylating STAT5A, whereas recombinant BTK proteins with SH1/Kinase domain mutations were not. In pull-down experiments, only full-length BTK and its SH1/Kinase domain (but not the pleckstrin homology, SH2, or SH3 domains) were capable of binding STAT5A. Ectopically expressed BTK Kinase domain was capable of tyrosine-phosphorylating STAT5A both in vitro and in vivo. BTK-mediated tyrosine phosphorylation of ectopically expressed wild type (but not Tyr694 mutant) STAT5A enhanced its DNA binding activity. In BTK-competent chicken B cells, anti-IgM-stimulated tyrosine phosphorylation of STAT5 protein was prevented by pretreatment with the BTK inhibitor LFM-A13 but not by pretreatment with the JAK3 inhibitor HI-P131. B cell antigen receptor ligation resulted in enhanced tyrosine phosphorylation of STAT5 in BTK-deficient chicken B cells reconstituted with wild type human BTK but not in BTK-deficient chicken B cells reconstituted with Kinase-inactive mutant BTK. Similarly, anti-IgM stimulation resulted in enhanced tyrosine phosphorylation of STAT5A in BTK-competent B cells from wild type mice but not in BTK-deficient B cells from XID mice. In contrast to B cells from XID mice, B cells from JAK3 knockout mice showed a normal STAT5A phosphorylation response to anti-IgM stimulation. These findings provide unprecedented experimental evidence that BTK plays a nonredundant and pivotal role in B cell antigen receptor-mediated STAT5A activation in B cells.

  • an inhibitor of Janus Kinase 3 4 4 hydroxyphenylamino 6 7 dimethoxyquinazolin 1 ium chloride methanol solvate
    Acta Crystallographica Section C-crystal Structure Communications, 2000
    Co-Authors: Elise A Sudbeck, Jason D Jennissen, Fatih M. Uckun
    Abstract:

    The crystal structure of the title compound, C16H16N3O3+·Cl−·CH4O (WHI-P131, an inhibitor of Janus Kinase 3), contains four hydrogen bonds. There are two hydrogen bonds within the asymmetric unit, i.e. interactions between WHI-P131 OH and Cl−, and between methanol and Cl−. There is a third interaction between WHI-P131 NH and Cl− (related by a 21 screw) and a fourth between WHI-P131 NH and methanol (related by an n-glide). The hydrogen-bond pattern for these interactions can be described by the first-level hydrogen-bond graph-set notation D11(2)D11(2)D11(2)D11(2). The second-level graph-set notation (for combinations of two hydrogen bonds) was determined to be D12(3)­D12(3)­D22(4)­D22(9)­D22(14)­C12(9).

Thomas Hoock - One of the best experts on this subject based on the ideXlab platform.

  • discovery of vx 509 decernotinib a potent and selective Janus Kinase 3 inhibitor for the treatment of autoimmune diseases
    Journal of Medicinal Chemistry, 2015
    Co-Authors: Luc J Farmer, Mark W Ledeboer, Thomas Hoock, Michael J Arnost, Randy S Bethiel, Youssef L Bennani, J Black, Christopher L Brummel, Ananthsrinivas Chakilam, Warren Dorsch
    Abstract:

    While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine Kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling Kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this Kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft mo...

  • vx 509 decernotinib is a potent and selective Janus Kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease
    Journal of Pharmacology and Experimental Therapeutics, 2015
    Co-Authors: Sudipta Mahajan, Luc J Farmer, James K Hogan, Dina Shlyakhter, Luke Oh, Francesco G Salituro, Thomas Hoock
    Abstract:

    Cytokines, growth factors and other chemical messengers rely on a class of intracellular non-receptor tyrosine Kinases known as Janus Kinases (JAKs) to rapidly transduce intracellular signals. A number of these cytokines are critical for lymphocyte development and mediating immune responses. JAK3 is of particular interest due to its importance in immune function and its expression, which is largely confined to lymphocytes, thus limiting the potential impact of JAK3 inhibition on non-immune physiology. The aim of this study was to evaluate the potency and selectivity of the investigational JAK3 inhibitor VX-509 (decernotinib) against JAK3 Kinase activity and inhibition of JAK3-mediated signaling in vitro and JAK3-dependent physiological processes in vivo. These results demonstrate that VX-509 potently inhibits JAK3 in enzyme assays (K i =2.5 nM + 0.7 nM) and cellular assays dependent on JAK3 activity (IC 50 range, 50-170 nM), with limited or no measurable potency against other JAK isotypes or non-JAK Kinases. VX-509 also showed activity in two animal models of aberrant immune function. VX-509 treatment resulted in dose-dependent reduction in ankle swelling and paw weight and improved paw histopathology scores in the rat collagen-induced arthritis (CIA) model. In a mouse model of oxazolone-induced delayed-type hypersensitivity (DTH), VX-509 reduced the T-cell-mediated inflammatory response in skin. These findings demonstrate that VX-509 is a selective and potent inhibitor of JAK3 in vitro and modulates pro-inflammatory response in models of immune-mediated diseases such as CIA and DTH. The data support evaluation of VX-509 for treatment of patients with autoimmune and inflammatory diseases such as rheumatoid arthritis.

Robert A. Kirken - One of the best experts on this subject based on the ideXlab platform.

  • selective inhibitor of Janus tyrosine Kinase 3 pnu156804 prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin
    Blood, 2002
    Co-Authors: Stanislaw M Stepkowski, Rebecca Erwincohen, Fariba Behbod, Mou Er Wang, Neelam Tejpal, Zsuzsanna S Nagy, Barry D Kahan, Xienui Qu, Robert A. Kirken
    Abstract:

    Janus Kinase 3 (Jak3) is a cytoplasmic tyrosine (Tyr) Kinase associated with the interleukin-2 (IL-2) receptor common gamma chain (gc) that is activated by multiple T-cell growth factors (TCGFs) such as IL-2, -4, and -7. Using human T cells, it was found that a recently discovered variant of the undecylprodigiosin family of antibiotics, PNU156804, previously shown to inhibit IL-2‐induced cell proliferation, also blocks IL-2‐mediated Jak3 auto-tyrosine phosphorylation, activation of Jak3 substrates signal transducers and activators of transcription (Stat) 5a and Stat5b, and extracellular regulated Kinase 1 (Erk1) and Erk2 (p44/p42). Although PNU156804 displayed similar efficacy in blocking Jak3-dependent T-cell proliferation by IL-2, -4, -7, or -15, it was more than 2-fold less effective in blocking Jak2-mediated cell growth, its most homologous Jak family member. A 14-day alternate-day oral gavage with 40 to 120 mg/kg PNU156804 extended the survival of heart allografts in a dose-dependent fashion. In vivo, PNU156804 acted synergistically with the signal 1 inhibitor cyclosporine A (CsA) and additively with the signal 3 inhibitor rapamycin to block allograft rejection. It is concluded that inhibition of signal 3 alone by targeting Jak3 in combination with a signal 1 inhibitor provides a unique strategy to achieve potent immunosuppression. (Blood. 2002;99: 680-689)

  • selective inhibitor of Janus tyrosine Kinase 3 pnu156804 prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin
    Blood, 2002
    Co-Authors: Stanislaw M Stepkowski, Rebecca Erwincohen, Fariba Behbod, Mou Er Wang, Neelam Tejpal, Zsuzsanna S Nagy, Barry D Kahan, Robert A. Kirken
    Abstract:

    Janus Kinase 3 (Jak3) is a cytoplasmic tyrosine (Tyr) Kinase associated with the interleukin-2 (IL-2) receptor common gamma chain (gc) that is activated by multiple T-cell growth factors (TCGFs) such as IL-2, -4, and -7. Using human T cells, it was found that a recently discovered variant of the undecylprodigiosin family of antibiotics, PNU156804, previously shown to inhibit IL-2‐induced cell proliferation, also blocks IL-2‐mediated Jak3 auto-tyrosine phosphorylation, activation of Jak3 substrates signal transducers and activators of transcription (Stat) 5a and Stat5b, and extracellular regulated Kinase 1 (Erk1) and Erk2 (p44/p42). Although PNU156804 displayed similar efficacy in blocking Jak3-dependent T-cell proliferation by IL-2, -4, -7, or -15, it was more than 2-fold less effective in blocking Jak2-mediated cell growth, its most homologous Jak family member. A 14-day alternate-day oral gavage with 40 to 120 mg/kg PNU156804 extended the survival of heart allografts in a dose-dependent fashion. In vivo, PNU156804 acted synergistically with the signal 1 inhibitor cyclosporine A (CsA) and additively with the signal 3 inhibitor rapamycin to block allograft rejection. It is concluded that inhibition of signal 3 alone by targeting Jak3 in combination with a signal 1 inhibitor provides a unique strategy to achieve potent immunosuppression. (Blood. 2002;99: 680-689)

  • functional uncoupling of the Janus Kinase 3 stat5 pathway in malignant growth of human t cell leukemia virus type 1 transformed human t cells
    Journal of Immunology, 2000
    Co-Authors: Rebecca A Erwin, Robert A. Kirken, Lihua Wang, Yuling Wang, William L Farrar
    Abstract:

    Human T cell leukemia virus type 1 (HTLV-1) transforms cytokine-dependent T lymphocytes and causes adult T cell leukemia. Janus tyrosine Kinase (Jak)3 and transcription factors Stat5a and Stat5b are essential for the proliferation of normal T cells and are constitutively hyperactivated in both HTLV-1-transformed human T cell lines and lymphocytes isolated from HTLV-1-infected patients; therefore, a critical role for the Jak3-Stat5 pathway in the progression of this disease has been postulated. We recently reported that tyrphostin AG-490 selectively blocked IL-2 activation of Jak3/Stat5 and growth of murine T cell lines. Here we demonstrate that disruption of Jak3/Stat5a/b signaling with AG-490 (50 μM) blocked the proliferation of primary human T lymphocytes, but paradoxically failed to inhibit the proliferation of HTLV-1-transformed human T cell lines, HuT-102 and MT-2. Structural homologues of AG-490 also inhibited the proliferation of primary human T cells, but not HTLV-1-infected cells. Disruption of constitutive Jak3/Stat5 activation by AG-490 was demonstrated by inhibition of 1) tyrosine phosphorylation of Jak3, Stat5a (Tyr 694 ), and Stat5b (Tyr 699 ); 2) serine phosphorylation of Stat5a (Ser 726 ) as determined by a novel phosphospecific Ab; and 3) Stat5a/b DNA binding to the Stat5-responsive β-casein promoter. In contrast, AG-490 had no effect on DNA binding by p50/p65 components of NF-κB, a transcription factor activated by the HTLV-1-encoded phosphoprotein, Tax. Collectively, these data suggest that the Jak3-Stat5 pathway in HTLV-1-transformed T cells has become functionally redundant for proliferation. Reversal of this functional uncoupling may be required before Jak3/Stat5 inhibitors will be useful in the treatment of this malignancy.

  • tyrphostin ag 490 inhibits cytokine mediated jak3 stat5a b signal transduction and cellular proliferation of antigen activated human t cells
    Journal of Leukocyte Biology, 1999
    Co-Authors: Robert A. Kirken, Rebecca A Erwin, Lihua Wang, Fariba Behbod, Dennis D Taub, William J Murphy, Federica Pericle, William L Farrar
    Abstract:

    Janus Kinase 3 (JAK3) is a cytoplasmic tyrosine Kinase required for T cell development and activated by cytokines that utilize the interleu- kin-2 (IL-2) receptor common gamma chain (gc). Genetic inactivation of JAK3 is manifested as se- vere combined immunodeficiency disease (SCID) in humans and mice. These findings have suggested that JAK3 represents a pharmacological target to control certain lymphoid-derived diseases. Here we provide novel evidence that AG-490 potently inhib- its the autoKinase activity of JAK3 and tyrosine phosphorylation and DNA binding of signal trans- ducer and activator of transcription 5a and 5b (STAT5a/b). Similar inhibitory effects were ob- served with other cytokines that use gc. AG-490 also inhibited IL-2-mediated proliferative growth in human T cells with an IC50 5 25 mM that was partially recoverable. Moreover, we demonstrate that this inhibitor prevented tetanus toxoid antigen- specific T cell proliferation and expansion but failed to block activation of Zap70 or p56Lck after anti-CD3 stimulation of human T cells. Taken together, these findings suggest that AG-490 inhib- its the JAK3-mediated Type II signaling pathway but not the T cell receptor-derived Type I pathway and possesses therapeutic potential for T cell- derived pathologies such as graft-versus-host dis- ease, allergy, and autoimmune disorders. J. Leu- koc. Biol. 65: 891-899; 1999.

Luc J Farmer - One of the best experts on this subject based on the ideXlab platform.

  • discovery of vx 509 decernotinib a potent and selective Janus Kinase 3 inhibitor for the treatment of autoimmune diseases
    Journal of Medicinal Chemistry, 2015
    Co-Authors: Luc J Farmer, Mark W Ledeboer, Thomas Hoock, Michael J Arnost, Randy S Bethiel, Youssef L Bennani, J Black, Christopher L Brummel, Ananthsrinivas Chakilam, Warren Dorsch
    Abstract:

    While several therapeutic options exist, the need for more effective, safe, and convenient treatment for a variety of autoimmune diseases persists. Targeting the Janus tyrosine Kinases (JAKs), which play essential roles in cell signaling responses and can contribute to aberrant immune function associated with disease, has emerged as a novel and attractive approach for the development of new autoimmune disease therapies. We screened our compound library against JAK3, a key signaling Kinase in immune cells, and identified multiple scaffolds showing good inhibitory activity for this Kinase. A particular scaffold of interest, the 1H-pyrrolo[2,3-b]pyridine series (7-azaindoles), was selected for further optimization in part on the basis of binding affinity (Ki) as well as on the basis of cellular potency. Optimization of this chemical series led to the identification of VX-509 (decernotinib), a novel, potent, and selective JAK3 inhibitor, which demonstrates good efficacy in vivo in the rat host versus graft mo...

  • vx 509 decernotinib is a potent and selective Janus Kinase 3 inhibitor that attenuates inflammation in animal models of autoimmune disease
    Journal of Pharmacology and Experimental Therapeutics, 2015
    Co-Authors: Sudipta Mahajan, Luc J Farmer, James K Hogan, Dina Shlyakhter, Luke Oh, Francesco G Salituro, Thomas Hoock
    Abstract:

    Cytokines, growth factors and other chemical messengers rely on a class of intracellular non-receptor tyrosine Kinases known as Janus Kinases (JAKs) to rapidly transduce intracellular signals. A number of these cytokines are critical for lymphocyte development and mediating immune responses. JAK3 is of particular interest due to its importance in immune function and its expression, which is largely confined to lymphocytes, thus limiting the potential impact of JAK3 inhibition on non-immune physiology. The aim of this study was to evaluate the potency and selectivity of the investigational JAK3 inhibitor VX-509 (decernotinib) against JAK3 Kinase activity and inhibition of JAK3-mediated signaling in vitro and JAK3-dependent physiological processes in vivo. These results demonstrate that VX-509 potently inhibits JAK3 in enzyme assays (K i =2.5 nM + 0.7 nM) and cellular assays dependent on JAK3 activity (IC 50 range, 50-170 nM), with limited or no measurable potency against other JAK isotypes or non-JAK Kinases. VX-509 also showed activity in two animal models of aberrant immune function. VX-509 treatment resulted in dose-dependent reduction in ankle swelling and paw weight and improved paw histopathology scores in the rat collagen-induced arthritis (CIA) model. In a mouse model of oxazolone-induced delayed-type hypersensitivity (DTH), VX-509 reduced the T-cell-mediated inflammatory response in skin. These findings demonstrate that VX-509 is a selective and potent inhibitor of JAK3 in vitro and modulates pro-inflammatory response in models of immune-mediated diseases such as CIA and DTH. The data support evaluation of VX-509 for treatment of patients with autoimmune and inflammatory diseases such as rheumatoid arthritis.

Paul S Changelian - One of the best experts on this subject based on the ideXlab platform.

  • cartilage preservation by inhibition of Janus Kinase 3 in two rodent models of rheumatoid arthritis
    Arthritis Research & Therapy, 2008
    Co-Authors: Anthony J Milici, Elizabeth M Kudlacz, Laurent Audoly, Samuel H Zwillich, Paul S Changelian
    Abstract:

    CP-690550 is a small molecule inhibitor of Janus Kinase 3 (JAK3), a critical enzyme in the signaling pathway of multiple cytokines (interleukin (IL)-2, -7, -15 and -21) that are important in various T cell functions including development, activation and homeostasis. The purpose of this study was to evaluate CP-690550 in murine collagen-induced (CIA) and rat adjuvant-induced (AA) models of rheumatoid arthritis (RA). CIA and AA were induced using standard protocols and animals received the JAK3 inhibitor via osmotic mini-pump infusion at doses ranging from 1.5–15 mg/kg/day following disease induction. Arthritis was assessed by clinical scores in the CIA models and paw swelling monitored using a plethysmometer in the AA model until study conclusion, at which time animals were killed and evaluated histologically. CP-690550 dose-dependently decreased endpoints of disease in both RA models with greater than 90% reduction observed at the highest administered dose. An approximate ED50 of approximately 1.5 mg/kg/day was determined for the compound based upon disease endpoints in both RA models examined and corresponds to CP-690550 serum levels of 5.8 ng/ml in mice (day 28) and 24 ng/ml in rats (day 24). The compound also reduced inflammatory cell influx and joint damage as measured histologically. Animals receiving a CP-690550 dose of 15 mg/k/d showed no histological evidence of disease. The efficacy observed with CP-690550 in CIA and AA suggests JAK3 inhibition may represent a novel therapeutic target for the treatment of RA.

  • immunosuppression by the jak3 inhibitor cp 690 550 delays rejection and significantly prolongs kidney allograft survival in nonhuman primates
    Transplantation, 2005
    Co-Authors: Dominic C Borie, Paul S Changelian, M J Larson, Ricardo T Paniagua, John P Higgins, Bari Holm, Andrew Campbell, Macy Lau, Sally Zhang, Mona G Flores
    Abstract:

    BACKGROUND Janus Kinase 3 (JAK3) mediates signal transduction from cytokine receptors using the common chain (gammac). Because mutations in genes encoding gammac or JAK3 result in immunodeficiency, we investigated the potential of a rationally designed inhibitor of JAK3, CP-690,550, to prevent renal allograft rejection in nonhuman primates. METHODS Life-supporting kidney transplantations were performed between mixed leukocyte reaction-mismatched, ABO blood group-matched cynomolgus monkeys. Animals were treated with CP-690,550 (n = 18) or its vehicle (controls, n = 3) and were euthanized at day 90 or earlier if there was allograft rejection. RESULTS Mean survival time (+/- standard error of mean) in animals treated with CP-690,550 (53 +/- 7 days) was significantly longer than in control animals (7 +/- 1 days, P=0.0003) and was positively correlated with exposure to the drug (r = 0.79, P < 0.01). Four treated animals were euthanized at 90 days with a normal renal function and low-grade rejection at final pathology. Occurrence of rejection was significantly delayed in treated animals (46 +/- 7 days from transplantation vs. 7 +/- 1 days in controls, P = 0.0003). Persistent anemia, polyoma virus-like nephritis (n = 2), and urinary calcium carbonate accretions (n = 3) were seen in animals with high exposure. Natural killer cell and CD4 and CD8 T-cell numbers were significantly reduced in treated animals. Blood glucose, serum lipid levels, and arterial blood pressure were within normal range in treated animals, and no cancers were demonstrated. CONCLUSIONS CP-690,550 is the first reported JAK3 inhibitor combining efficacy and good tolerability in a preclinical model of allotransplantation in nonhuman primates and thus has interesting potential for immunosuppression in humans.

  • prevention of organ allograft rejection by a specific Janus Kinase 3 inhibitor
    Science, 2003
    Co-Authors: Paul S Changelian, Mark Edward Flanagan, Douglas J Ball, Craig R Kent, Kelly S Magnuson, William H Martin, Bonnie J Rizzuti, Perry S Sawyer, Bret D Perry, William H Brissette
    Abstract:

    Because of its requirement for signaling by multiple cytokines, Janus Kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolongedsurvival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associatedwith hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation andin other clinical settings.