Chapter 22. Cytokine Modulation as a Medicinal Chemistry Target

Chapter 22. Cytokine Modulation as a Medicinal Chemistry Target Kelvin Cooper and Hiroko Masamune Central Research Division, Pfizer Inc, Groton, CT 06340

Introduction - The cytokines are the protein hormones that orchestrate leukocyte function during the active phases of natural and specific immunity in addition to regulating immune and inflammatory responses. Two fundamental features are clearly emerging as characteristic of all the cytokines: 1) pleiotropy -each cytokine has more than one biological function, and 2) redundancy - each function is mediated by more than one cytokine. Furthermore, each cytokine is produced by and acts on multiple cell types, often influencing the function of other cytokines. Thus, these far ranging activities have made cytokines challenging targets for drug research. This chapter will review recent progress made in the discovery of modulators of cytokine function with emphasis on the activity of small molecules. Clinical use of specific biologicals such as antibodies, soluble receptors, or recombinant cytokines will also be covered. The cytokine receptors were reviewed in Volume 26 of this series (1). Interleukin 1 - IL-1 exists in two different forms, IL-la and IL-lp, and is primarily produced by macrophages. It plays a central role in both inflammatory and immunological responses and has been implicated in a wide range of human diseases such as hemodynamic shock, arthritis, inflammatory bowel disease, and lethal sepsis. The structure and biological functions of IL-1 have been reviewed (2). A wide range of small molecules has been found to modulate IL-1 synthesis or release and was reviewed in volume 25 of this series (3). This section will update and extend that review.

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Pentamidine 1blocks (ICs0 = 1 pM) the post translational modification of prolL-1a to the mature 17 kDa form in lipopolysaccharide (LPS)-stimulated mouse macrophages without affecting phagocytosis or la antigen expression (4).IX 207-887 2 inhibits release, but not synthesis of IL-1 from human monocytes and mouse macrophages with ICs0’sof 30 and 60 pM, respectively, without affecting secretion of IL-6 and tumor necrosis factor (TNF) (5). SKF 105,809 3 is converted in vivo to the combined cyclooxygenaseAipoxygenase(COILO) inhibitor SKF 105,561 :and shows unique anti-inflammatory activity in murine models that are normally resistant to CO inhibitors (6).This activity is due to its in vitro inhibition of IL-1 production (7), although the mechanism of action is unknown. A series of naphthalene propenoic acids 5 blocks IL-1 generation in vitro in LPS-stimulated human monocytes and rat macrophages, and in vivo in a rat CMC-LPS air-pouch model (8). Acetoxy E 5090 6 serves as a prodrug for the active hydroxy derivativez, the most potent compound in the series

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(9). The anti-allergy compound (3-949 S, an inhibitor of histamine, leukotriene and thromboxane production from human mast cells, has also been shown to be a weak inhibitor of IL-1 release from human peripheral blood leukocytes (10). In contrast, the COlLO inhibitor, tebufelone 2, enhances LPS-stimulatedIL-1 and TNF production by human peripheral blood mononuclear cells at concentrations similar to those which block the production of leukotriene (LT) synthesis. The mechanism of increased production is a post translational event since IL-1 or TNF mRNA levels were not affected , is an inhibitor of IL-1, IL-6, and TNF production in (11). The novel steroid, mometasone furoate 1O LPS-stimulated mouse leukemia cells, being 100-200X more potent than dexamethasone 1_1 (12).

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L1 In addition to their direct effect on IL-1 production, gold sodium thiomalate 12 and auranofin 12 inhibit rinterferon (Y-IFN)enhancement of IL-1 production (13). The immunosuppressantFK506 1 4 (vide infre), in addition to its effect on T-cell responses, blocks the synthesis and production of IL-1 from LPS-stimulated human monocytes and alveolar macrophages (14). The protease which cleaves prolL-lp to the mature 17 kDa form represents an attractive target for drug intervention.The substrate specificity of this enzyme, IL-1 converting enzyme (ICE), has been determined (15) and patent applications on the sequence, as well as on a series of peptidic inhibitors 12, have been filed (16). Human derived IL-1 receptor antagonist (IL-lra), a 152 amino acid peptide (17), binds to the receptor with high affinity (Kd = 150 pM)(18).

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lnterleukin 2 - IL-2 plays an integral role in the clonal expansion of T-lymphocytes after antigen stimulation (19,20). In addition, it stimulates the growth and differentiationof a variety of other lymphocytes, including B cells, natural killer (NK) cells, and lymphokine-activatedkiller (LAK) cells. 11-2 exists as a 15 kDa monomeric glycoprotein and recently, an FDA advisory committee recommended approval for ChironlCetus’ recombinant IL-2 (Proleukin) for the treatment of renal cell carcinoma, an often fatal disease (21). The efficacy of IL-2 has been investigated in a number of other cancerous states (22), but unfortunately, it appears that patients receiving high doses of IL-2 suffer from a number of serious side effects (23), as well as experiencing disease relapse (24). Several approaches are being explored to decrease the limiting toxicity of IL-2, including administering low-dose IL-2 (25), combining IL-2with ibuprofen (26), and examining the possible mechanismsof toxicity (27). The IL-2 receptor (IL-2R) is also the focus of much research (28).

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Although the direct involvement of IL-2 has been difficult to assess (19), it is implicated in a number of autoimmune diseases such as rheumatoid arthritis (RA) and in patients undergoing organ transplants. Inhibition of 11-2 production has thus been a major objective of drug discovery and is thought to be one of the modes of action of cyclosporin A 12, the current drug of choice in antirejection therapy (29). Unfortunately, the use of 13 is dose-limitingdue to systemic toxicity, particularly nephrotoxicity. Another macrolide of interest is FK506 13, which appears to be 10-1OOX more potent that 12 (30) and appears to inhibit IL-2production,even though it binds to a different cytosolic receptor than 15 (31). Early clinical'data on 13 suggest that it is also an effective immunosuppressant with a side effect profile which may limit its use (32). A drug which is being developed as therapy for RA, bucillamine 12,has been found to inhibit the production of IL-2 by 50% at 100 p M (33). Similar effects were seen with sulphasalazine 12, an inhibits IL-2 production anti-rheumatic drug used to treat ulcerative colitis (34). Dexamethasone at much lower concentrations (35). Compound 11 also has a significant effect on IL-2R production and IL-2 mRNA levels.

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There have been several other compounds that have been examined pre-clinically for irnmunosuppressive effects. Recent reports suggest that protein kinase C (PKC) is directly involved in the production of IL-2 (36); accordingly, H-7 12,a PKC inhibitor, was found to suppress IL-2 production an anti-allergy compound, blocks the release of 11-2 from conby 70% at 10 pM (37). '3-959 canavalin A-stimulated rat splenocytes (ICs0= 19.1 pM) and human lymphocytes(ICs0= 23.1 p M ) (38). This effect is considerably less potent than that produced with or 15, albeit comparable to NSAID's such as indomethacin. 1,25-DihydroxyvitaminDo2J. an immunomodulatory hormone, also shows potent effects on IL-2 production (39).

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In contrast, up-regulation of IL-2 can also be induced with small molecules. Ciprofloxacin 22, a quinolone antibacterial, significantly increases IL-2 production in phytohemagglutinin-stimulated human peripheral blood lymphoctes (3-5X increase at 50-100 pglml) (40). Increased IL-2 production in the spleen of tumor-bearing mice is likewise seen upon treatment by RS-0481 23 (41).

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lnterleukin 3 - IL-3 is a 23 kDa glycoprotein whose general function is to induce proliferation of early hematopoieticprogenitor cells (19, 42). It is closely related to granulocyte-macrophagecolony stimulating factor (GM-CSF) and often has similar activity. One of the modes of action attributed to IL-3 and GM-CSF is to enhance histamine synthesis in the progenitor cells (42). Histamine plays a role not only in allergic reactions, but also in signalling between leukocytes involved in imrnunologically mediated inflammation. It has been suggested that histamine is an important mediator in inducible hematopoiesisand as such, is the rationale for the immunomodulatoryeffects of such H2 receptor antagonists as cimetidine 24 (43). Other features of 11-3 activity include downregulation of the expression of IL-2R (44) and the involvement oftyrosine kinases (45).

lnterleukin 4 - IL-4 is a 20 kDa peptide, produced principally by T cells, which plays a key role in B-cell growth and is the sole cytokine responsible for initiationof IgE synthesis, implicatingit in allergic diseases and parasitic infections. Its immunoregulatoryfunctions and potential application in cancer therapy have been reviewed (46, 47). Several structure function studies have been carried out on human IL-4. Using secondary structure predictions,site directed mutagenesis and CD spectroscopy, a model of the protein has been generated and predicts an all parallel four helix globular protein with two overhand loop connections(48). The protein containsthree disulphide links but mutagenesis studies show that only one bridge, Cys46 to Cys99, is essential for biologicalactivity (49). Polyclonal antibodiesto a series of segments coveringthe entire sequence have been used to attempt to identify the receptor binding region of the peptide (50). Antibodies to Leu52-Cys65 and Lys61-Phe82 bind the most effectively to IL-4. In addition, an anti-idiotypic antibody to the Lys61-Phe82 sequence antagonized IL-4 binding to its receptor without binding to 11-4 which suggests that receptor binding is localizedto that region. Two small segments of IL-4,Ala70-Arg88 and Asn89Glu122, show agonist activity in a fibroblast chemotaxis assay, with the former showing the most potent effects (51). Few small molecules have been reported to show modulatoryeffects on IL-4 activity. IPD-l151T

25 has been reported to inhibit mitogen-inducedIL-4 production (52). Dexamethasone 12 treatment

of a homogeneous T cell line simultanoeusly inhibits IL-2 production and stimulates IL-4 production from the antigen-stimulatedcells and this modulatoryeffect can be inhibited by the steroid antagonist RU486 (53).Another steroid, dihydrotestosterone26,inhibits IL-4 production, as well as IL-5 and y-INF production, by anti-CDrstimulated mouse T cells. Although testosterone has no effect on isolated T-cells, in the presenceof macrophages which possess Sor-reductase, it also inhibits IL-4 production (54). Cyclosporin A 12 inhibits both 11-4 and IL-4 receptor expression in anti-CD3-stimulatedhuman peripheral blood mononuclear cells (55).

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lnterleukin 5 - IL-5 is produced principally by T cells and plays a key role in eosinophil and B-cell proliferation and differentiation. Hence, this cytokine is also thought to have a role in allergic diseases and parasitic infections (56). Structure function studies of humanlmouse chimeric IL-5 molecules have defined the C-terminus as the receptor binding region and together with the dimer studies suggest that IL-5 may function as a bifunctional ligand inducing cross linking in two IL-5 receptors (57).In agreement with the chimeric protein work, C-terminus truncated human IL-5 failed to induce B cell differentiation (58).No selective, small molecule modulators of IL-5 have been disclosed, although the inhibition of IL-5-induced eosinophil survival is blocked by high concentrations of nedocromil 27 (59). lnterleukin 6 - IL-6 is a 26 kDa peptide produced by macrophages,T cells, and fibroblasts. Along with IL-1 and TNF, IL-6 is a major mediator of the acute phase response to infection or injury. Its abnormal production is thought to play a key role in inflammatory and autoimmune diseases (60). In addition, the potential uses of IL-6 and antagonists of IL-6 as therapeutants have been reviewed (61). A variety of structure function studies on human IL-6 have been performedallowing some predictions about the receptor binding region to be made. More recently, a combination of nmr and sitedirected mutagenesisstudies support a role for Met162 in receptor binding and additionally suggest that Leu159 and Leu166 are also important for binding (62).

Dihydroxyvitamin D321 and the analog MC 903 28 inhibit the production of 11-6 by LPSstimulated human mononuclear cells (63). whereas hydroxyvitamin D329 has no effect, suggesting a specific action through the vitamin D3receptor. Additionally, has been shown to reduce the levels of IL-6 in psoriatic lesions (64). Dexamethasone and cortisol inhibit the productionof 11-6 from LPSstimulated mouse macrophages and human monocytes, endothelial cells and fibroblasts via stimulation of the glucocorticoid receptor (65). Prostaglandin E2 (PGE2) is a potent inhibitor of IL-6 production in endotoxin-stimulated Kupffer cells and thus the CO inhibitor indomethacin can enhance IL-6 production (66). Similarly, treatment with ibuprofen prior to endotoxin adminstration leads to elevated levels of 11-6 as well as elevated levels of TNF-a, presumably by inhibition of PGEpsynthesis (67). In vivo treatment with the peripheral benzodiazepine Ro5-4864 0, blocks the ex vivo production of IL-1, IL-6, and TNFw by LPS-stimulatedmouse spleen macrophages. In contrast, peritoneal macrophages from the same mice are unaffected (68). Retinoic acid and menthol inhibit IL-6 receptor (IL-6R) expression in human leucocytes via down regulation of IL-6R mRNA; this effect may explain their anti-proliferative effects (69).

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Interleukin 7 - IL-7 is a 25 kDa protein derived from stromal cells. It stimulates the proliferation of pre-B cells, thymocytes, and mature T cells (70, 71), as well as stimulating the tumoricidal activity of monocytes (72) and the killing ability of cytotoxic T lymphocytes (73). The IL-7 receptor has recently

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been cloned and characterized, showing it to be a member of a receptor superfamily (74). In addition to the membrane bound receptor forms, a cDNA was isolated that encoded for a soluble form of the IL-7 receptor. IL-7 has also been shown to be effective as a therapeutic agent in vivo, in cyclophosphamide-induced lymphopenia in mice (75). Treatment with 200 mglkg i.p. of cyclophosphamide causes a substantial decrease in the cellularity of the bone marrow and lymphoid organs as reflected by a drop in T cell and B cell numbers. Administration of IL-7 (500 ng, s.c.) results in a more rapid return to the normal range of cellularity in the spleen and mesenteric lymph node but not in the thymus or bone marrow. lnterleukin 8 - IL-8 is a monocyte-derivedchemotactic factor for neutrophils and hence, has also been described as Neutrophil Activating Factor (NAF), Neutrophil Activating Peptide (NAP), and Neutrophil Chemotactic Factor (NCF). It is a 72 amino acid peptide and in addition to its chemotactic ability for neutrophils, it also induces neutrophil activation (76, 77). IL-8 acts as a “later stage” chemotactic factor, on the order of hours, after its expression is induced by other cytokines (78). Elevated levels of IL-8 have been determined in a number of disease states, such as rheumatoid arthritis (79), chronic airway diseases (EO), and idiopathic pulmonary fibrosis (80). The role of calcium in IL-8 induced migration of lymphocytes was investigated using a series of calcium channel antagonists (81). Verapamil, nifedipine, and diltiazem are all potent inhibitors of stimulated migration (lCIo’s of 10 nM, 60 nM, and 10 nM, respectively), implying a role for calcium channel activation. IL-8 induced migration is also inhibited by PKC inhibitors H-7 19, Ro series 31, and sphingosine 2(82). An endogenous immunomodulator, dihydroxyvitamin DO inhibits IL-la induced IL-8 production and mRNA expression in keratinocytes, fibroblasts, and peripheral blood monocytes, but not in endothelial cells (83). Antiinflammatory agents have also been found to be efficacious;the 5-LO/CO inhibitor BI-L-936s 3inhibits the release of 11-8from LPS-stimulated THP-1 cells (84). This compound has an EDs0of 16.5 mglkg in the rat carrageenan-induced paw edema model (85).

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lnterleukin 10 -First described as Cytokine Synthesis Inhibitory Factor, 11-10 is a 35 kDa homodimeric protein which is secreted by TH2(helper T) cells and mast cells. As its earlier name implies, IL-10 is involved in the cross-regulationbetweenTH1 and TH2cells by inhibiting cytokine synthesis by TH1 clones (86). This cross-regulation is important since TH1 and TH2 activities are often mutually exclusive (delayed type hypersensitivity and antibody responses, respectively). In addition, IL-10 appears to be a growth cofactor for mature and immature T cells ( 8 7 , a cytotoxic T cell differentiation factor (88), and in conjunction with 11-3and/or 11-4, a stimulatory factor for mast cells (89). Interestingly, it was discovered that the BCRFl gene of the Epstein Barr virus (EBV) has high homology to human IL-10 (90). Recombinant BCRF1 protein inhibits interferon production by human T cells stimulated either with phytohemagglutinin, CD3antibodies, or IL-2, a property shared by 11-10. One of the actions of -/-IFN is that it inhibits viral replication and in synergy with tumor necrosis factor, selectively kills virus-infected cells. This suggests that EBV has captured and conserved the mammalian genome for the purpose of reducing the anti-viral effects of the host immune response. Tumor Necrosis Factor-a - TNF-a is a 157 amino acid peptide produced by macrophages, keratinocytes and T cells. This cytokine plays a central role in host defense mechanisms and has been implicated in shock, chronic inflammation, and other autoimmune diseases. Its structure, function, and potential clinical uses have been reviewed (91, 92, 93). Histamine inhibits LPS-stimulatedTNF-a synthesis in human peripheral blood mononuclear cells via H2-receptormediated TNF-a mRNA reduction, and suggests that local release of histamine may limit TNF-a release (94). Thalidomide 33, used as a treatment for erythema nodosum leprosum, has

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been found to reduce the production of TNF-a in LPS-stimulatedhuman monocytes (95). Compound

34 has no effect on general protein synthesis and also does not inhibit IL-1 or GM-CSF production.

Dexamethasone inhibits TNF-a production from LPS-stimulatedKupffer cells, an effect which can be blocked with the steroid antagonist RU 486 (96). Cyclosporin A 13 inhibits TNF-or release from mouse macrophages,without suppresion of TNF-(YmRNA levels or reductionof intracellular TNF-a a known in vitro inhibitor of TNF-a production, has been (97). The methyl xanthine pentoxifylline3, shown to protect animals from LPS-inducedTNF-a productionand subsequent death (98). In similar studies in man, 35 inhibits the increase in serum concentrations of TNF-a in endotoxin treated volunteers (99). However, the acute rise in IL-6 levels is unaffected, indicating a selective action of 35. The mechanism by which 35 works has been linked to its phosphodiesterase(PDE) inhibitory activity, and this is supported by the ability of the PDE inhibitors theophylline 3s and isobutylmethylxanthine 7 to also suppress TNF-a production from LPS-stimulated mouse macrophages (100). Compounds is also capable of reversing TNF-a-induced inhibiton of f-Met-Leu-Phe-mediatedlymphocyte chemotaxis (101). TNF-a upregulation of adhesion molecule (ICAM-1) expression on human umbilical vein endothelial cells is mediated at least partially by PKC's, since the inhibitors are inhibitory (102). staurosporinone 38 and H-7

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Granulocyte-Macrophageand Granulocyte Colony Stimulating Factors - The colony stimulating factors (CSF's) are a family of regulatory glycoproteinsthat stimulatethe productionof lineage specific cells from committed hematopoietic progenitor cells. The effects of GM-CSF and G-CSF are far ranging and affect virtually every function of the granulocyte and macrophage that has been studied (103, 104). In addition, recent evidence suggests a role for GM-CSF in eosinophil chemotaxis (105). GMCSF has been detected in a number of disease states, such as RA (106) and psoriasis (107). For neutropenic disease states, however, recombinant CSF's are being investigated as therapeutic agents because of their stimulatory effects (108, 109, 110). Because of the ability of multiple cytokines to accelerate hematopoiesis and known synergism in vim, fusion proteins such as GM-CSF/IL-3 are also being developed (111).

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A synthetic peptide, SKF-107,647 has been found to be efficacious in stimulating general colony stimulating activity (CSA) (112). Single injections of 1-10 nglkg of 39 increase CSA levels in mice by 400-6000/0, and multiple doses of 10 nglkg qd x 7 increase peritoneal macrophage superoxide production and candidacidal activity. In another approach, significant enhancement of GMCSF-stimulatedneutrophil responses are observed by the preincubation of whole blood with H-7 12, suggesting that a protein kinase-mediatedphosphorylation step is important in the down-regulation of neutrophil responses to GM-CSF (113).

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When alloreactive T helper cell clones are treated with cyclosporin A 1 2 ,even in the presence of exogenous IL-2, GM-CSF secretion is inhibited (114). Coinciding with the observation of leukotrienes in vivo in patients being treated with GM-CSF (115), the cytotoxicity in monocytes which is elicited

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by GM-CSF is found to be augmented by indomethacin, a CO inhibitor, and found to be suppressed an LO inhibitor (116).Dexamethasone inhibits the prolongation by nordihydroguaiaretic acid of eosinophil survival caused by GM-CSF (117).

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Interferon - IFN is a generic term for a family of proteins with a multitude of effects including virus inhibition, oncogene suppression, and slowing of cell proliferation. The IFN’s are comprised of 01IFN, p-IFN, Y-IFN and d F N , each with several subtypes which bind to at least two diferent types of receptors (1 18).In chronic viral infections, such as hepatitis 8, a-IFN has shown positive benefit, but is usually ineffective in acute viral infection (1 19). Both p- and +FN have been extensively tested in the treatment of various cancers. However, the outcome is variable with the best results obtained in therapy of residual malignancies (120,121). Much work has been done on the mapping of the effector regions of the IFN’s using synthetic fragments and epitope mapping with monoclonal antibodies. Structure function studies with a-IFN have recently been summarized and extended (122). When IFN was last reviewed in this series, a considerable number of interferon inducers were described (123).However, the early promise of this area has not come to fruition; very few reports of these agents having appeared in recent years. Nevertheless, one such agent continues to be of interest; CL 246,738 9 is a potent inducer of IFN in vivo, elevating circulating levels of IFN and activating natural killer cells. Compound 41 is currently in Phase I clinical trials (124).

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Conclusion - The controlled modulation of cytokine function presents an enormous challenge to the medicinal chemist. Some progress has been made in defining agents which interfere with cytokine activity but with few exceptions, these compounds have not been designed for that purpose. This has meant that selectivity for modulation of an individual cytokine is rare, which in turn has hampered the execution of pharmacological experiments which define the precise roles of the cytokines. Without doubt, the future lies with purpose-designed antagonists, agonists, inhibitors, or enhancers. These studies will provide not only the pharmacological tools but also the future drugs for the treatment of immunological, inflammatory, and oncological diseases. References 1.

2. 3. 4. 5. 6.

7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

17. 18. 19. 20.

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