Promiscuous drugs as therapeutics for chemokine receptors

Richard Horuk

doi:10.1017/S1462399409000921

Promiscuous drugs as therapeutics for chemokine receptors

Published online by Cambridge University Press: 06 January 2009

Richard Horuk

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Richard Horuk: Affiliation:
Department of Pharmacy, Touro University, 1310 Johnson Lane, Vallejo, CA 94592, USA. Tel: +1 925 708 0358; E-mail: horuk@pacbell.net

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Abstract

Chemokine receptor antagonists that held much promise for the treatment of autoimmune and inflammatory diseases have recently performed poorly in clinical trials, resulting in disappointment for both pharmaceutical companies and patients. This review focuses on the redundancy of the molecular target as one potential reason for the failure of some of these antagonists to fulfil their initial promise, and discusses the use of drugs that are capable of interacting with more than one drug target – so-called promiscuous drugs – as possible approaches to overcome this difficulty. Several clinically approved promiscuous drugs, such as aspirin and olanzapine, are already used successfully. This review discusses examples of promiscuous drugs for G-protein-coupled receptors, including progress in developing dual-specific chemokine receptor antagonists, and considers evidence for the possible therapeutic utility of such drugs.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 11 , July 2009 , e1

DOI: https://doi.org/10.1017/S1462399409000921 [Opens in a new window]
Copyright: Copyright © Cambridge University Press 2009

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References

1Ribeiro, S. and Horuk, R. (2005) Chemokine Receptor Antagonists from the Bench to the Clinic (Hannan, A. and Engelhardt, B., series eds), Wiley-VCH, Weinheim, GermanyCrossRef Google Scholar

2Baggiolini, M. (1998) Chemokines and leukocyte traffic. Nature 392, 565-568CrossRef Google Scholar PubMed

3Carvalho-Pinto, C. et al. (2004) Leukocyte attraction through the CCR5 receptor controls progress from insulitis to diabetes in non-obese diabetic mice. European Journal of Immunology 34, 548-557CrossRef Google Scholar PubMed

4Kikuchi, Y. et al. (2004) Fractalkine and its receptor, CX3CR1, upregulation in streptozotocin-induced diabetic kidneys. Nephron Experimental Nephrology 97, e17-25CrossRef Google Scholar PubMed

5Haringman, J.J. et al. (2006) A randomized controlled trial with an anti-CCL2 (anti-monocyte chemotactic protein 1) monoclonal antibody in patients with rheumatoid arthritis. Arthritis and Rheumatism 54, 2387-2392CrossRef Google Scholar PubMed

6Sawai, H. et al. (2007) Fractalkine mediates T cell-dependent proliferation of synovial fibroblasts in rheumatoid arthritis. Arthritis and Rheumatism 56, 3215-3225CrossRef Google Scholar PubMed

7Trebst, C. et al. (2001) CCR1+/CCR5+ mononuclear phagocytes accumulate in the central nervous system of patients with multiple sclerosis. American Journal of Pathology 159, 1701-1710CrossRef Google Scholar PubMed

8Eltayeb, S. et al. (2007) Temporal expression and cellular origin of CC chemokine receptors CCR1, CCR2 and CCR5 in the central nervous system: insight into mechanisms of MOG-induced EAE. Jourmal of Neuroinflammation 4, 14CrossRef Google Scholar PubMed

9Rottman, J.B. et al. (2000) Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. European Journal of Immunology 30, 2372-23773.0.CO;2-D>CrossRef Google Scholar PubMed

10Fife, B.T. et al. (2000) CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. Journal of Experimental Medicine 192, 899-905CrossRef Google Scholar PubMed

11Fife, B.T. et al. (2001) CXCL10 (IFN-gamma-inducible protein-10) control of encephalitogenic CD4+ T cell accumulation in the central nervous system during experimental autoimmune encephalomyelitis. Journal of Immunology 166, 7617-7624CrossRef Google Scholar PubMed

12Vestergaard, C. et al. (2004) Expression of CCR2 on monocytes and macrophages in chronically inflamed skin in atopic dermatitis and psoriasis. Acta Dermato-Venereologica 84, 353-358CrossRef Google Scholar PubMed

13Gombert, M. et al. (2005) CCL1-CCR8 interactions: an axis mediating the recruitment of T cells and Langerhans-type dendritic cells to sites of atopic skin inflammation. Journal of Immunology 174, 5082-5091CrossRef Google Scholar PubMed

14Yuan, Q. et al. (2007) CCR4-dependent regulatory T cell function in inflammatory bowel disease. Journal of Experimental Medicine 204, 1327-1334CrossRef Google Scholar PubMed

15Singh, U.P. et al. (2008) CXCL10+ T cells and NK cells assist in the recruitment and activation of CXCR3+ and CXCL11+ leukocytes during Mycobacteria-enhanced colitis. BMC Immunology 9, 25CrossRef Google Scholar PubMed

16Santella, J.B. 3rd et al. (2008) From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis. Bioorganic and Medicinal Chemistry Letters 18, 576-585CrossRef Google Scholar PubMed

17Gauvreau, G.M. et al. (2008) Antisense therapy against CCR3 and the common beta chain attenuates allergen-induced eosinophilic responses. American Journal of Respiratory and Critical Care Medicine 177, 952-958CrossRef Google Scholar PubMed

18Liehn, E.A. et al. (2008) Ccr1 deficiency reduces inflammatory remodelling and preserves left ventricular function after myocardial infarction. Journal of Cellular and Molecular Medicine 12, 496-506CrossRef Google Scholar PubMed

19Combadiere, C. et al. (2008) Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 117, 1649-1657CrossRef Google Scholar PubMed

20Schnickel, G.T. et al. (2008) Combined CXCR3/CCR5 blockade attenuates acute and chronic rejection. Journal of Immunology 180, 4714-4721CrossRef Google Scholar PubMed

21Horuk, R. et al. (2001) A non-peptide functional antagonist of the CCR1 chemokine receptor is effective in rat heart transplant rejection. Journal of Biological Chemistry 276, 4199-4204CrossRef Google Scholar PubMed

22Jamieson, W.L. et al. (2008) CX3CR1 is expressed by prostate epithelial cells and androgens regulate the levels of CX3CL1/fractalkine in the bone marrow: potential role in prostate cancer bone tropism. Cancer Research 68, 1715-1722CrossRef Google Scholar PubMed

23Zlotnik, A. (2008) New insights on the role of CXCR4 in cancer metastasis. Journal of Pathology 215, 211-213CrossRef Google Scholar PubMed

24Doranz, B.J. et al. (1996) A dual-tropic primary HIV-1 isolate that uses fusin and the β-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Cell 85, 1149-1158CrossRef Google Scholar PubMed

25Feng, Y. et al. (1996) HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science 272, 872-877CrossRef Google Scholar PubMed

26Murphy, P.M. et al. (2000) International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacological Reviews 52, 145-176Google Scholar PubMed

27Hopkins, A.L. and Groom, C.R. (2002) The druggable genome. Nature Reviews Drug Discovery 1, 727-730CrossRef Google Scholar PubMed

28Lamb, E. (2007) Top 200 prescription drugs of 2006. Pharmacy Times May 1st, 34-37Google Scholar

29DiMasi, J.A., Hansen, R.W. and Grabowski, H.G. (2003) The price of innovation: new estimates of drug development costs. Journal of Health Economics 22, 151-185CrossRef Google Scholar

30Schuster, D., Laggner, C. and Langer, T. (2005) Why drugs fail–a study on side effects in new chemical entities. Current Pharmaceutical Design 11, 3545-3559CrossRef Google Scholar

31Zipp, F. et al. (2006) Blockade of chemokine signaling in patients with multiple sclerosis. Neurology 67, 1880-1883CrossRef Google Scholar PubMed

32Brown, M.F. et al. (2007) Piperazinyl CCR1 antagonists–optimization of human liver microsome stability. Bioorganic and Medicinal Chemistry Letters 17, 3109-3112CrossRef Google Scholar PubMed

33Vann, L. (2007) End of 2007 brings extra activity. Autoimmune Drug Focus 37, 1Google Scholar

34Braddock, M. (2007) 11th annual Inflammatory and Immune Diseases Drug Discovery and Development Summit 12–13 March 2007San Francisco, USA. Expert Opinion on Investigational Drugs 16, 909-917CrossRef Google Scholar

35Johnson, M. et al. (2007) Discovery and optimization of a series of quinazolinone-derived antagonists of CXCR3. Bioorganic and Medicinal Chemistry Letters 17, 3339-3343CrossRef Google Scholar PubMed

36Sospedra, M. and Martin, R. (2005) Immunology of multiple sclerosis. Annual Review of Immunology 23, 683-747CrossRef Google Scholar PubMed

37Frantz, S. (2005) Drug discovery: playing dirty. Nature 437, 942-943CrossRef Google Scholar PubMed

38Roth, B.L., Sheffler, D.J. and Kroeze, W.K. (2004) Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nature Reviews Drug Discovery 3, 353-359CrossRef Google Scholar PubMed

39Overington, J.P., Al-Lazikani, B. and Hopkins, A.L. (2006) How many drug targets are there? Nature Reviews Drug Discovery 5, 993-996CrossRef Google Scholar

40Vainio, H. and Morgan, G. (1997) Aspirin for the second hundred years: new uses for an old drug. Pharmacology and Toxicology 81, 151-152CrossRef Google Scholar PubMed

41Katler, E. and Weissmann, G. (1977) Steroids, aspirin, and inflammation. Inflammation 2, 295-307CrossRef Google Scholar PubMed

42Serhan, C.N., Haeggstrom, J.Z. and Leslie, C.C. (1996) Lipid mediator networks in cell signaling: update and impact of cytokines. FASEB Journal 10, 1147-1158CrossRef Google Scholar PubMed

43Clavel, F. and Hance, A.J. (2004) HIV drug resistance. New England Journal of Medicine 350, 1023-1035CrossRef Google Scholar PubMed

44Bymaster, F.P. et al. (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14, 87-96CrossRef Google Scholar PubMed

45Kroeze, W.K. et al. (2003) H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 28, 519-526CrossRef Google Scholar PubMed

46Mendel, D.B. et al. (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clinical Cancer Research 9, 327-337Google Scholar PubMed

47Potapova, O. et al. (2006) Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248. Molecular Cancer Therapeutics 5, 1280-1289CrossRef Google Scholar

48Cella, D. et al. (2008) Quality of life in patients with metastatic renal cell carcinoma treated with sunitinib or interferon alfa: results from a phase III randomized trial. Journal of Clinical Oncology 26, 3763-3769CrossRef Google Scholar PubMed

49Tolle, M. et al. (2007) Sphingosine-1-phosphate and FTY720 as anti-atherosclerotic lipid compounds. European Journal of Clinical Investigation 37, 171-179CrossRef Google Scholar PubMed

50Charo, I.F. and Taubman, M.B. (2004) Chemokines in the pathogenesis of vascular disease. Circulation Research 95, 858-866CrossRef Google Scholar PubMed

51Morphy, R., Kay, C. and Rankovic, Z. (2004) From magic bullets to designed multiple ligands. Drug Discovery Today 9, 641-651CrossRef Google Scholar PubMed

52Murugesan, N. et al. (2002) Discovery of N-isoxazolyl biphenylsulfonamides as potent dual angiotensin II and endothelin A receptor antagonists. Journal of Medicinal Chemistry 45, 3829-3835CrossRef Google Scholar PubMed

53Murugesan, N. et al. (2005) Dual angiotensin II and endothelin A receptor antagonists: synthesis of 2'-substituted N-3-isoxazolyl biphenylsulfonamides with improved potency and pharmacokinetics. Journal of Medicinal Chemistry 48, 171-179CrossRef Google Scholar

54Kowala, M.C. et al. (2004) Novel dual action AT1 and ETA receptor antagonists reduce blood pressure in experimental hypertension. Journal of Pharmacology and Experimental Therapeutics 309, 275-284CrossRef Google Scholar PubMed

55Ohshima, E. et al. (1993) Dibenz[b,e]oxepin derivatives: novel antiallergic agents possessing thromboxane A2 and histamine H1 dual antagonizing activity. Journal of Medicinal Chemistry 36, 417-420CrossRef Google Scholar PubMed

56McHugh, D. et al. (2006) Novel compounds that interact with both leukotriene B4 receptors and vanilloid TRPV1 receptors. Journal of Pharmacology and Experimental Therapeutics 316, 955-965CrossRef Google Scholar PubMed

57Suzuki, K. et al. (2007) A dual antagonist for chemokine CCR3 receptor and histamine H1 receptor. European Journal of Pharmacology 563, 224-232CrossRef Google Scholar PubMed

58Simons, F.E. and Simons, K.J. (1994) The pharmacology and use of H1-receptor-antagonist drugs. New England Journal of Medicine 330, 1663-1670Google Scholar PubMed

59Vaidehi, N. et al. (2006) Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation. Journal of Biological Chemistry 281, 27613-27620CrossRef Google Scholar PubMed

60Barnes, P.J. (1995) Inhaled glucocorticoids for asthma. New England Journal of Medicine 332, 868-875CrossRef Google Scholar PubMed

61Clemens, J.J. et al. (2005) Synthesis of 4(5)-phenylimidazole-based analogues of sphingosine-1-phosphate and FTY720: discovery of potent S1P1 receptor agonists. Bioorganic and Medicinal Chemistry Letters 15, 3568-3572CrossRef Google Scholar PubMed

62Fredriksson, R. et al. (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Molecular Pharmacology 63, 1256-1272CrossRef Google Scholar PubMed

63Schwartz, T.W. and Rosenkilde, M.M. (1996) Is there a ‘lock’ for all agonist ‘keys’ in 7TM receptors? Trends in Pharmacological Sciences 17, 213-216CrossRef Google Scholar

64Blanpain, C. et al. (2003) The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle. Journal of Biological Chemistry 278, 5179-5187CrossRef Google Scholar PubMed

65Ji, T.H., Grossmann, M. and Ji, I. (1998) G protein-coupled receptors. I. Diversity of receptor-ligand interactions. Journal of Biological Chemistry 273, 17299-17302CrossRef Google Scholar PubMed

66Watson, C. et al. (2005) The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor. Molecular Pharmacology 67, 1268-1282CrossRef Google Scholar PubMed

67Ahuja, S.K., Gao, J.L. and Murphy, P.M. (1994) Chemokine receptors and molecular mimicry. Immunology Today 15, 281-287CrossRef Google Scholar PubMed

68McFadden, G. et al. (1998) Virus-encoded receptors for cytokines and chemokines. Semin Cell Developmental Biology 9, 359-368CrossRef Google Scholar PubMed

69McFadden, G. and Murphy, P.M. (2000) Host-related immunomodulators encoded by poxviruses and herpesviruses. Current Opinion in Microbiology 3, 371-378CrossRef Google Scholar PubMed

70Frauenschuh, A. et al. (2007) Molecular cloning and characterization of a highly selective chemokine-binding protein from the tick Rhipicephalus sanguineus. Journal of Biological Chemistry 282, 27250-27258CrossRef Google Scholar PubMed

71de Mendonca, F.L. et al. (2005) Site-directed mutagenesis of CC chemokine receptor 1 reveals the mechanism of action of UCB 35625, a small molecule chemokine receptor antagonist. Journal of Biological Chemistry 280, 4808-4816CrossRef Google Scholar PubMed

72Vedani, A. et al. (2005) Novel ligands for the chemokine receptor-3 (CCR3): a receptor-modeling study based on 5D-QSAR. Journal of Medicinal Chemistry 48, 1515-1527CrossRef Google Scholar PubMed

73Naya, A. et al. (2003) Structure-Activity Relationships of 2-(Benzothiazolylthio)acetamide Class of CCR3 Selective Antagonist. Chemical and Pharmaceutical Bulletin (Tokyo) 51, 697-701CrossRef Google Scholar PubMed

74Sabroe, I. et al. (2000) A small molecule antagonist of chemokine receptors CCR1 and CCR3. Potent inhibition of eosinophil function and CCR3-mediated HIV-1 entry. Journal of Biological Chemistry 275, 25985-25992CrossRef Google Scholar PubMed

75Baba, M. et al. (1999) A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proceedings of the National Academy of Sciences of the United States of America 96, 5698-5703CrossRef Google Scholar PubMed

76Seto, M. et al. (2006) Highly potent and orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety. Journal of Medicinal Chemistry 49, 2037-2048CrossRef Google Scholar PubMed

77Miltz, W. (2008) CCR2/CCR5 antagonists: a new approach for the treatment of autoimmune diseases. Presented at 235th ACS National Meeting (6–10 April 2008; New Orleans, LA, USA), http://oasys2.confex.com/acs/235nm/techprogram/P1158061.HTM Google Scholar

78Walters, I. et al. (2008) Evaluation of a series of bicyclic CXCR2 antagonists. Bioorganic and Medicinal Chemistry Letters 18, 798-803CrossRef Google Scholar PubMed

79Pease, J.E. and Horuk, R. (2005) CCR1 antagonists in clinical development. Expert Opinion on Investigational Drugs 14, 785-796CrossRef Google Scholar PubMed

80Ribeiro, S. and Horuk, R. (2005) The clinical potential of chemokine receptor antagonists. Pharmacology and Therapeutics 107, 44-58CrossRef Google Scholar PubMed

81Saederup, N. et al. (2008) Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in CCR2-/- mice: evidence for independent chemokine functions in atherogenesis. Circulation 117, 1642-1648CrossRef Google Scholar PubMed

82Pyo, R. et al. (2004) Inhibition of intimal hyperplasia in transgenic mice conditionally expressing the chemokine-binding protein M3. American Journal of Pathology 164, 2289-2297CrossRef Google Scholar PubMed

83Parry, C.M. et al. (2000) A broad spectrum secreted chemokine binding protein encoded by a herpesvirus. Journal of Experimental Medicine 191, 573-578CrossRef Google Scholar PubMed

84Kim, W.J. et al. (2003) MCP-1 deficiency is associated with reduced intimal hyperplasia after arterial injury. Biochemical and Biophysical Research Communications 310, 936-942CrossRef Google Scholar PubMed

85Gao, W. et al. (2001) Beneficial effects of targeting CCR5 in allograft recipients. Transplantation 72, 1199-1205CrossRef Google Scholar PubMed

86Hancock, W.W. et al. (2000) Requirement of the chemokine receptor CXCR3 for acute allograft rejection. Journal of Experimental Medicine 192, 1515-1520CrossRef Google Scholar PubMed

87Bacus, S.N.L.S., and Yarden, Y. (2005) The era of ErbB-receptor-targeted therapies:advances toward personalized medicine. Personalized Medicine 2, 301-315CrossRef Google Scholar

88Palczewski, K. et al. (2000) Crystal structure of rhodopsin: A G protein-coupled receptor. Science 289, 739-745CrossRef Google Scholar PubMed

89Cherezov, V. et al. (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science 318, 1258-1265CrossRef Google Scholar PubMed

90Rasmussen, S.G. et al. (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature 450, 383-387CrossRef Google Scholar PubMed

91Rosenbaum, D.M. et al. (2007) GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science 318, 1266-1273CrossRef Google Scholar PubMed

92Brinkmann, V. et al. (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. Journal of Biological Chemistry 277, 21453-21457CrossRef Google Scholar PubMed

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Promiscuous drugs as therapeutics for chemokine receptors

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