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Artículo destacado 
Drug News & Perspectives LOOKING AHEAD The success of CP-690550 in animal organ transplant models makes prevention of allograft rejection the most likely application of JAK inhibitors. JAK Protein Kinase Inhibitors by James E. Thompson Summary In humans, the Janus protein tyrosine kinase family (JAKs) contains four members: JAK1, JAK2, JAK3 and TYK2. JAKs phosphorylate signal transducers and activators of transcription (STATs) simultaneously with other phosphorylations required for activation, and there are several cellular mechanisms in place to inhibit JAK/STAT signaling. That one might be able to modulate selected JAK/STAT-mediated cellular signals by inhibiting JAK kinase activity to effect a positive therapeutic outcome is a tantalizing prospect, as yet incompletely realized. While current data suggest no therapeutic use for JAK1 and TYK2 inhibition, JAK2 inhibition seems a promising but not definitively tested mechanism for treatment of leukemia. More promising, however, are data indicating a possible therapeutic use of JAK3 inhibition. The restriction of the JAK3-deficient phenotype to the hematopoietic system and the resulting profound immune suppression suggest that JAK3 could be a target for immunosuppressive therapies used to prevent organ transplant rejection. © 2005 Prous Science. All rights reserved. In humans, the Janus protein tyrosine kinase family (JAKs) contains four members: JAK1, JAK2, JAK3 and TYK2.1-4 JAK3 is the most recently discovered and was found in a search for the genetic origins of X-linked severe combined immune deficiency.5 No new members have been reported after sequencing of the human genome, so these four likely comprise the entire family. Each is a single polypeptide chain between 1,100 and 1,200 amino acids in length. The N terminal half of the JAKs contains five homologous domains (JH3-JH7 domains) involved in interaction with the intracellular domains of multichain cytokine and hormone receptors, followed by a "kinase-like" domain (JH2), which lacks conserved amino acids essential for protein kinase activity. The roughly 380 amino acids at the C-terminus comprise the catalytically active protein kinase domain (JH1).6 JAKs phosphorylate signal transducers and activators of transcription (STATs) simultaneously with other phosphorylations required for activation. In the case of the high-affinity interleukin-2 (IL-2) receptor, JAK1 associates with the β-chain, JAK3 with the γ-chain and the α-chain has no associated kinase. Upon IL-2 binding, two tyrosines on the β-chain, 392 and 510, are phosphorylated and can serve as docking sites for STAT5a, STAT5b or STAT3.7 The STATs are then phosphorylated on tyrosine by JAK1 or JAK3, which have themselves been phosphorylated,8 each presumably by the other. The STATs contain a tyrosine phosphorylation site and a phosphotyrosine binding SH2 domain. After phosphorylation, the SH2 domain of a STAT binds to the phosphotyrosine of another, and vice versa, forming a homo- or heterodimer, which is then imported to the nucleus to activate transcription.9,10 An alternative mechanism for STAT activation has just been discovered in cell culture systems: acetylation of a single lysine can lead to STAT3 dimerization and transcriptional activation.11 There are several cellular mechanisms in place to inhibit JAK/STAT signaling. The JAB or SOCS proteins bind to the phosphorylated residues of the JAK kinase domain, which prevents JAK-catalyzed phosphorylation of STATs and also targets the JAKs for proteasomal degradation.12-14 Protein inhibitors of activation of STATs can bind to activated STATs and prevent DNA binding.15 STAT5 itself is target for processing and inactivation by a unique protease.16,17 SHP phosphatases contain SH2 phosphotyrosine recognition domains that allow association and subsequent dephosphorylation of an activated JAK.18-21 Small molecule approaches to enhance these physiological mechanisms are not obvious. The number and diversity of extracellular molecules that require the JAK/STAT pathway for signal transductions is remarkable: all interferon (α, β or γ) signaling,1,22 all shared γ-chain cytokine receptors and gp130-utilizing cytokines, 23,24 and hormones including growth hormone, prolactin, leptin, erythropoietin and thrombopoietin activate the JAK/STAT pathway.25-30 That one might be able to modulate selected JAK/STAT-mediated cellular signals by inhibiting JAK kinase activity to effect a positive therapeutic outcome is a tantalizing prospect, as yet incompletely realized. When considering the therapeutic potential of JAK inhibition, the most reliable information comes from genetic approaches. As will be discussed, small molecule inhibitors of the JAKs described in the scientific literature have not always been broadly characterized in terms of their specificity, which clouds interpretation of cellular and in vivo experiments with them. A broad protein kinase selectivity panel is essential if one is to interpret results from experiments with small molecule protein kinase inhibitors. The signal transduction literature is rife with experiments using protein kinase inhibitors without acknowledgment of those inhibitors' possible lack of selectivity. Some of these inhibitors have later been found to inhibit many protein kinases.31,32 JAK3 JAK3 is associated only with the shared γ chain of interleukin receptors for IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21, receptors whose expression is limited to the hematopoietic system.28 Some human patients presenting with a severe combined immune compromise were found to have mutations in JAK3,5,33 and this phenotype has been reproduced by genetic deletion of JAK3 in rodents.34,35 The restriction of the JAK3-deficient phenotype to the hematopoietic system and the resulting profound immune suppression suggest that JAK3 could be a target for immunosuppressive therapies used to prevent organ transplant rejection.36 To date, the most potent JAK3 inhibitor is CP-690550 (Fig. 1), described by Changelian et al.37 This molecule has 1 nM affinity for JAK3 (Table I) and is 20-fold selective with respect to JAK2. Other protein kinases are inhibited even less potently by CP-690550.37 Following CP-690550 in potency is pyridone 6 (Fig. 1), described by this author and others,38 at 5 nM (Table I). pyridone 6 lacks the selectivity within the JAK family that CP-690550 possesses; it inhibits JAK2 and TYK2 with greater affinity than JAK3.38 WHI-P131 (Fig. 1) was originally characterized by measuring inhibition of autophosphorylation of kinases of interest via autoradiography39as having IC50 78 µM. Titration of protein kinase activity with more quantitative assays by Changelian et al. allowed determination of JAK3 IC50 > 1 µM, and JAK1 and JAK2 IC50 > 10 µM. No in vitro assessments of the potency of PNU-156804 (Fig. 1) have been carried out.
Fig. 1. JAK inhibitors.
JAK3 is essential to IL-2 receptor signaling, and T cells rendered dependent on IL-2 for proliferation in culture should stop dividing in the presence of JAK3 inhibitors. CP-690550 blocks proliferation of phytohemagglutinin and IL-2-treated primary lymphocytes with IC50 = 11 nM.37 Cross-species activity was evident in mixed-lymphocyte reactions (MLR), where CP-690550 inhibited human, monkey and murine MLRs with IC50 < 115 nM.37 Pyridone 6 inhibited IL-2-stimulated proliferation of CTLL with IC50 = 100 nM.38 Both pyridone 6 and CP-690550 were tested in cellular assays in which JAK3 has no role: pyridine 6 inhibits phorbol ester-stimulated proliferation of CTLL with IC50 > 3 µM, and CP-690550 does not inhibit serum-induced proliferation of fibroblasts at 10 µM.37,38 WHI-P131 was found to have IC50 > 10,000 nM for inhibition of IL-2-stimulated primary lymphocytes and also to inhibit phosphotyrosine accumulation in epidermal growth factor (EGF)-stimulated 3T3 fibroblasts with IC50 = 400 nM.37 WHI-P131's inhibition of EGF stimulation is unexpected for a JAK3 inhibitor and occurs at a concentration lower than the in vitro IC50 for inhibition of JAK3. It has previously been shown to stabilize mast cells and inhibit proliferation of glioblastoma cells, as well as to block platelet aggregation.40-43 In light of the data from Changelian et al., it is possible that the cellular effects of WHI-P131 owe to action on targets other than JAK3. CP-690550 was studied as a single drug to prevent rejection of an allogeneic kidney transplant in cynomolgus monkeys and murine heterotopic heart transplants. In both cases it was found to have dose-dependent efficacy.37,44 Drug doses were adjusted during the course of the monkey experiment to maintain plasma levels at 200-400 or 50-100 ng/ml. CP-690550 allowed 50% of kidney grafted monkeys to survive for 90 days at the high dose and 30% to survive for 90 days at the low dose; untreated animals did not survive longer than 10 days.37 The murine heterotopic hearts were found to have fewer infiltrating cells per area and to have diminished levels of cytotoxic effector molecule (e.g., Fas ligand) and chemokines (e.g., RANTES B) mRNA.37 More detailed analysis of the immunosuppression in mice showed that the drug synergized with ciclosporin and caused a 96% drop in splenic NK1 T cells, with more modest decreases in CD4+ and CD8+ T cells.44 In the monkey, circulating NK cells were also diminished by CP-690550, with little effect seen on CD8+ effector memory T cells.45 The effects seen on NK1.1 T cells are attributable to inhibition of IL-15 signaling and could lead to an impaired antiviral response. JAK2 is activated in response to erythropoietin, which is required for production of erythrocytes, and JAK2-deficient mice die at birth in part because of an inability to produce these essential cells.46 CP-690550 did cause lower hemoglobin in monkeys treated with high doses, but at low doses hemoglobin levels were normal by the end of the 90-day study, with some decline observed at 45 days.37 WHI-P131 has been studied in mouse models of graft versus host disease, autoimmune diabetes and anaphylactic shock.41,47,48 Its pharmacokinetics have also been described.49 Although assigning all the actions of WHI-P131 to inhibition of JAK3 is not supported by the data from Changelian et al.,37 the in vivo efficacy in the described models is not in dispute. Finally, the natural product PNU-156804, which resembles one half of a porphyrin ring, is frequently cited as a specific inhibitor of JAK350-52 but has just a twofold selectivity compared with its inhibition of prolactin-stimulated growth, which is mediated by JAK2.50 As in the case of WHI-P131, the in vivo activity of PNU-156804 is not in dispute but is not unambiguously attributable to inhibition of JAK3. NC-1153 (Fig. 1) has been described as a specific JAK3 inhibitor, with minimally 40-fold selectivity over JAK2 as assessed by inhibition of autophosphorylation.53 It also has shown efficacy in preventing rejection of rat kidney allografts and may induce graft tolerance, since animals treated with NC-1153 can receive heart transplants from the kidney-donating animal but not from a different donor animal without further immunosuppres- sive drugs.53 The toxicological profile of NC-1153 is encouraging; no changes are observed in serum lipid profile in NC-1153-dosed animals. In the same study, triglyceride increases of 2.5-fold were observed in ciclosporin-treated animals.53 NC-1153 did not show signs of renal toxicity, which is a liability of ciclosporin. JAK1 JAK1 is found on all type II cytokine receptors,22,54 all interleukin receptors that recruit the shared γ chain55 and receptors utilizing the gp130 chain.56 Genetic ablation of JAK1 in mice yields runted pups that die shortly after birth, and cells derived from those embryos fail to respond to interferons α and γ (type II cytokines) and IL-7 (a γ chain utilizing interleukin), and show diminished STAT activation in response to IL-6 or LIF (gp130-utilizing cytokines).57 Jak1-deficient cells transformed with the v-abl oncogene have a diminished responsiveness to apoptosis-induced interferon γ and are more tumorogenic than similar wild-type cells.58 This suggests a role for JAK1 in tumor surveillance. The accumulated data on JAK1 suggests that inhibition of JAK1 would not be therapeutic and should be avoided. No specific JAK1 inhibitors have been reported to date. CP-690550 inhibits JAK1 with an in vitro JAK1 IC50 = 112 nM, 100-fold higher than its JAK3 IC50. The trough levels in the autologous kidney transplant study were greater than 1 µM in some of the surviving animals, suggesting that peak levels might have been high enough to inhibit JAK1 in vivo, but in the absence pharmacodynamic assays for JAK1 inhibition in that study, no conclusions may be drawn about the safety of JAK1 inhibition. JAK2 Among the JAK2-dependent receptors are those JAKs required for some hormone signals (growth hormone, prolactin, leptin, erythropoietin and thrombopoietin). Although the array of signals transduced by JAK2 and the phenotype of the JAK2-deficient mouse suggests that inhibition of JAK2 would be deleterious,47 high-dose CP-690550-treated monkeys with plasma drug levels maintained at 5-50 times the in vitro IC50 for JAK2 presented with detectable but apparently not fatal anemia. This is germane, since there is a chromosomal rearrangement resulting in a TEL-JAK2 fusion protein in human leukemia.59-61 AG-490 (tyrphostin B42; Fig. 1) is frequently cited in the scientific literature and inhibits proliferation of leukemic cells.62,63 However, when tested in vitro, AG-490 inhibited JAK1 more potently than JAK2,37 calling into question the interpretation that its cellular or in vivo effects owe to JAK2 inhibition. Recently Flowers et al. used a peptide inhibitor of JAK2 as a mimic of an SOCS protein to inhibit interferon-stimulated MHC class I upregulation in cultured fibroblasts,64 which is a step toward non-ATP-competitive JAK inhibitors. Consideration of all current data identify JAK2 inhibition as a promising but not definitively tested mechanism for treatment of leukemia. TYK2 TYK2 has a role in interferon signaling,65 and mice deficient in TYK2 are markedly more susceptible to disease in lymphoma models.66 No specific TYK2 inhibitors have been reported to date, and current data do not suggest a therapeutic use for a TYK2 inhibitor. Future Prospects The success of CP-690550 in animal organ transplant models makes prevention of allograft rejection the most likely application of JAK inhibitors. Recruitment has begun for phase I human clinical trials to test efficacy, pharmacodynamics and pharmacokinetics of the combination of CP-690550, mycophenolate mofetil and prednisone. Transplant rejection is a life-threatening condition, and the most likely adverse events predicted from study of JAK biology--increased susceptibility to disease, anemia and decreased tumor surveillance--are already experienced by transplant patients. Selective inhibition of JAK3 may have a distinguishing advantage when compared with ciclosporin therapy if JAK3 inhibition does not cause the kidney toxicity seen in some ciclosporin-treated patients.67 The demonstrated selectivity of CP-690550 for JAK3 compared with a sampling of protein kinases and within the JAK family is an important demonstration of chemical tractability. Use of the knowledge gained in the development of CP-690550 will allow informed decisions as to whether JAK3 inhibition can be sufficiently safe for the treatment of autoimmune diseases. In addition, the well described JAK2 inhibition by CP-690550 may also guide estimation of a therapeutic index for JAK2 inhibition during leukemia treatment. As demonstrated by the Bcr-abl/c-kit/PDGFR protein kinase inhibitor Gleevec®, a lack of selectivity can sometimes lead to a new therapeutic indication.68 Note added in proof Two important developments have occurred during review of this manuscript. First, the structure of the JAK3 kinase domain in its activated form was determined by X-ray crystallography.69 Second, a somatic activating mutation of JAK2 was found to occur in 121 out of 164 patients with polycythemia vera, a disease which is marked by hyperproliferation of hematopoietic precursor cells.70 References 1. Leonard, W.J. Role of Jak kinases and STATs in cytokine signal transduction Int J Hematol 2001, 73: 271-7. 2. O'Shea, J.J., Pesu, M., Borie, D.C. and Changelian, P.S. A new modality for immunosuppression: Targeting the JAK/ STAT pathway. Nat Rev Drug Discov 2004, 3: 555-64. 3. Rawlings, J.S., Rosler, K.M. and Harrison, D.A. The JAK/STAT signaling pathway J Cell Sci 2004, 117: 1281-3. 4. Hombria, J.C. and Brown, S. 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Drug News & Perspectives
Vol. 18, No. 5, 2005, pp. 305-310
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