Hugh Rosen

Summary

Affiliation: The Scripps Research Institute
Country: USA

Publications

  1. pmc Actions of a picomolar short-acting S1P₁ agonist in S1P₁-eGFP knock-in mice
    Stuart M Cahalan
    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
    Nat Chem Biol 7:254-6. 2011
  2. ncbi request reprint The organization of the sphingosine 1-phosphate signaling system
    Hugh Rosen
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA, 92037, USA
    Curr Top Microbiol Immunol 378:1-21. 2014
  3. doi request reprint Sphingosine-1-phosphate and its receptors: structure, signaling, and influence
    Hugh Rosen
    Department of Chemical Physiology and Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
    Annu Rev Biochem 82:637-62. 2013
  4. ncbi request reprint Tipping the gatekeeper: S1P regulation of endothelial barrier function
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Trends Immunol 28:102-7. 2007
  5. ncbi request reprint Chemical approaches to the lysophospholipid receptors
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Prostaglandins Other Lipid Mediat 77:179-84. 2005
  6. doi request reprint Modulating tone: the overture of S1P receptor immunotherapeutics
    Hugh Rosen
    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Immunol Rev 223:221-35. 2008
  7. ncbi request reprint Egress: a receptor-regulated step in lymphocyte trafficking
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Immunol Rev 195:160-77. 2003
  8. pmc Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 100:10907-12. 2003
  9. ncbi request reprint Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm
    Hugh Rosen
    Department of Immunology and Committee for Advanced Human Therapeutics, The Scripps Research Institute, ICND 118 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Curr Opin Chem Biol 7:461-8. 2003
  10. doi request reprint Sphingosine 1-phosphate receptor signaling
    Hugh Rosen
    Departments of Chemical Physiology and Immunology and The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037, USA
    Annu Rev Biochem 78:743-68. 2009

Detail Information

Publications82

  1. pmc Actions of a picomolar short-acting S1P₁ agonist in S1P₁-eGFP knock-in mice
    Stuart M Cahalan
    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
    Nat Chem Biol 7:254-6. 2011
    ..We demonstrate differential downregulation of S1P(1) on lymphocytes and endothelia after agonist treatment...
  2. ncbi request reprint The organization of the sphingosine 1-phosphate signaling system
    Hugh Rosen
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA, 92037, USA
    Curr Top Microbiol Immunol 378:1-21. 2014
    ....
  3. doi request reprint Sphingosine-1-phosphate and its receptors: structure, signaling, and influence
    Hugh Rosen
    Department of Chemical Physiology and Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
    Annu Rev Biochem 82:637-62. 2013
    ..An array of genetic models allows analysis of integrated receptor function in vivo. We can now directly understand causal relationships among protein expression, signal, and control points in physiology and pathology...
  4. ncbi request reprint Tipping the gatekeeper: S1P regulation of endothelial barrier function
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Trends Immunol 28:102-7. 2007
    ....
  5. ncbi request reprint Chemical approaches to the lysophospholipid receptors
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Prostaglandins Other Lipid Mediat 77:179-84. 2005
    ..These developments, coupled with the availability of receptor knock-out mice, presage rapid progress in the field...
  6. doi request reprint Modulating tone: the overture of S1P receptor immunotherapeutics
    Hugh Rosen
    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Immunol Rev 223:221-35. 2008
    ....
  7. ncbi request reprint Egress: a receptor-regulated step in lymphocyte trafficking
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Immunol Rev 195:160-77. 2003
    ..This inhibition induces significant immunosuppression in models of transplantation and autoimmune tissue damage that may prove to be of clinical benefit...
  8. pmc Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 100:10907-12. 2003
    ..Inhibition of lymphocyte egress from thymus and lymph node can contribute synergistically to clinically useful immunosupression by disrupting recirculation of peripheral T cells...
  9. ncbi request reprint Sphingosine 1-phosphate pathway therapeutics: a lipid ligand-receptor paradigm
    Hugh Rosen
    Department of Immunology and Committee for Advanced Human Therapeutics, The Scripps Research Institute, ICND 118 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Curr Opin Chem Biol 7:461-8. 2003
    ..These approaches can potentially be extended to a broad, related family of G-protein-coupled receptors that share ligands and ligand similarities...
  10. doi request reprint Sphingosine 1-phosphate receptor signaling
    Hugh Rosen
    Departments of Chemical Physiology and Immunology and The Scripps Research Institute Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037, USA
    Annu Rev Biochem 78:743-68. 2009
    ....
  11. pmc Full pharmacological efficacy of a novel S1P1 agonist that does not require S1P-like headgroup interactions
    Pedro J Gonzalez-Cabrera
    Departments of Chemical Physiology and Immunology, Scripps Research Institute Molecular Screening Center, La Jolla, CA 92037, USA
    Mol Pharmacol 74:1308-18. 2008
    ..These data show that CYM-5442 activates S1P(1)-dependent pathways in vitro and to levels of full efficacy in vivo through a hydrophobic pocket separate from the orthosteric site of S1P binding that is headgroup-dependent...
  12. pmc S1P(1) receptor modulation with cyclical recovery from lymphopenia ameliorates mouse model of multiple sclerosis
    Pedro J Gonzalez-Cabrera
    Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA 92037, USA
    Mol Pharmacol 81:166-74. 2012
    ..S1P(1)-selective agonists that induce reversible lymphopenia while persisting in the CNS may be effective MS treatments...
  13. pmc Endogenous EPCR/aPC-PAR1 signaling prevents inflammation-induced vascular leakage and lethality
    Frank Niessen
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
    Blood 113:2859-66. 2009
    ..Thus, the activating proteases and selectivity in coupling to S1P receptor subtypes determine vascular PAR1 signaling specificity in systemic inflammatory response syndromes in vivo...
  14. ncbi request reprint Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo
    M Germana Sanna
    Department of Immunology and The Scripps Research Institute Molecular Screening Center, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    Nat Chem Biol 2:434-41. 2006
    ..Thus, chemical modulation reveals differences in S1P-S1P1 'set points' among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention...
  15. pmc Ligand-binding pocket shape differences between sphingosine 1-phosphate (S1P) receptors S1P1 and S1P3 determine efficiency of chemical probe identification by ultrahigh-throughput screening
    STEPHAN C SCHURER
    Department of Scientific Computing, The Scripps Research Institute, La Jolla, California and Jupiter, Florida, USA
    ACS Chem Biol 3:486-98. 2008
    ....
  16. pmc Sphingosine 1-phosphate receptor 1 (S1P(1)) upregulation and amelioration of experimental autoimmune encephalomyelitis by an S1P(1) antagonist
    Stuart M Cahalan
    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Mol Pharmacol 83:316-21. 2013
    ....
  17. pmc Discovery, design and synthesis of novel potent and selective sphingosine-1-phosphate 4 receptor (S1P₄-R) agonists
    Miguel Guerrero
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 22:537-42. 2012
    ..Remarkably, the molecules herein reported provide novel pharmacological tools to decipher the biological function and assess the therapeutic utility of the S1P(4)-R...
  18. ncbi request reprint CD69 down-modulation and inhibition of thymic egress by short- and long-term selective chemical agonism of sphingosine 1-phosphate receptors
    Christopher Alfonso
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Eur J Immunol 36:149-59. 2006
    ....
  19. pmc Local not systemic modulation of dendritic cell S1P receptors in lung blunts virus-specific immune responses to influenza
    David Marsolais
    Departments of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Mol Pharmacol 74:896-903. 2008
    ..Thus, our results suggest that locally delivered sphingosine analogs induce immunosuppression by modulating S1P receptors other than S1P(1) or S1P(2) on dendritic cells in the lungs after influenza virus infection...
  20. pmc Treatment with a sphingosine analog does not alter the outcome of a persistent virus infection
    Kevin B Walsh
    Department of Immunology and Microbial Science, The Scripps Research Institute, IMM 6, TSRI, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Virology 397:260-9. 2010
    ..Therefore, treatment with a sphingosine analog does not ameliorate persistent LCMV-Cl 13 infection...
  21. pmc Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection
    John R Teijaro
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
    Cell 146:980-91. 2011
    ..Modulation of endothelium with a specific agonist suggests that diseases in which amplification of cytokine storm is a significant pathological component could be chemically tractable...
  22. pmc A critical role for the sphingosine analog AAL-R in dampening the cytokine response during influenza virus infection
    David Marsolais
    Department of Chemical Physiology and Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 106:1560-5. 2009
    ..These data indicate that sphingosine analogs display useful potential for controlling the immunopathology caused by influenza virus...
  23. ncbi request reprint Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues
    Anthony S Don
    Departments of Immunology and Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 282:15833-42. 2007
    ....
  24. ncbi request reprint Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate
    M Germana Sanna
    Department of Immunology, The Center for Mass Spectrometry, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 279:13839-48. 2004
    ....
  25. pmc Potent and selective inhibitors of glutathione S-transferase omega 1 that impair cancer drug resistance
    Katsunori Tsuboi
    The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 133:16605-16. 2011
    ..Cancer cells treated with KT53 show heightened sensitivity to the cytotoxic effects of cisplatin, supporting a role for GSTO1 in chemotherapy resistance...
  26. pmc SAR analysis of innovative selective small molecule antagonists of sphingosine-1-phosphate 4 (S1P₄) receptor
    Mariangela Urbano
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 21:5470-4. 2011
    ..By expanding the molecular diversity within the hit-derived class, our SAR study provides innovative small molecule potent and selective S1P(4) antagonists suitable for in vivo pharmacological validation of the target receptor...
  27. ncbi request reprint Mapping pathways downstream of sphingosine 1-phosphate subtype 1 by differential chemical perturbation and proteomics
    Pedro J Gonzalez-Cabrera
    Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
    J Biol Chem 282:7254-64. 2007
    ..These data suggest that the hierarchy of ubiquitin recruitment to S1P(1) (AFD-R > S1P > SEW2871) correlates with the efficiency of lysosomal receptor degradation and reflects intrinsic differences between agonists...
  28. pmc SAR analysis of novel non-peptidic NPBWR1 (GPR7) antagonists
    Miguel Guerrero
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA
    Bioorg Med Chem Lett 23:614-9. 2013
    ....
  29. pmc Novel selective allosteric and bitopic ligands for the S1P(3) receptor
    Euijung Jo
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    ACS Chem Biol 7:1975-83. 2012
    ....
  30. pmc Confirming target engagement for reversible inhibitors in vivo by kinetically tuned activity-based probes
    Alexander Adibekian
    Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 134:10345-8. 2012
    ....
  31. ncbi request reprint S1P1-selective in vivo-active agonists from high-throughput screening: off-the-shelf chemical probes of receptor interactions, signaling, and fate
    Euijung Jo
    Department of Immunology, The Scripps Research Institute, 10550 North Torrey Pines Road, ICND 118, La Jolla, CA 92037, USA
    Chem Biol 12:703-15. 2005
    ....
  32. pmc S1P3 receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF
    Yasuhiro Gon
    Department of Immunology, Core Microscopy Facility, Helen L Dorris Child and Adolescent Neuro Psychiatric Disorder Institute, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 102:9270-5. 2005
    ..Because S1P3-null mice are resistant to S1P-induced pulmonary leakage, either alone or in the presence of TNF, S1P3 antagonism may be useful in protecting epithelial integrity in pulmonary disease...
  33. pmc Selective inhibitors and tailored activity probes for lipoprotein-associated phospholipase A(2)
    Joseph M G Nagano
    The Department of Chemical Physiology, The Scripps Research Institute, 10550 N Torrey Pines Rd La Jolla, CA 92037, USA
    Bioorg Med Chem Lett 23:839-43. 2013
    ..Our findings thus identify both inhibitors and chemoproteomic probes that are suitable for investigating Lp-PLA(2) function in biological systems...
  34. pmc Design, synthesis and SAR analysis of novel potent and selective small molecule antagonists of NPBWR1 (GPR7)
    Mariangela Urbano
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA
    Bioorg Med Chem Lett 22:7135-41. 2012
    ..This lead molecule may provide a pharmacological tool to clarify the molecular basis of the in vivo physiological function and therapeutic utility of NPBWR1 in diverse disease areas including inflammatory pain and eating disorders...
  35. pmc Dissecting influenza virus pathogenesis uncovers a novel chemical approach to combat the infection
    Michael B A Oldstone
    Viral Immunobiology Laboratory, Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
    Virology 435:92-101. 2013
    ..The functional mechanism of S1P receptor agonist(s) action and the predominant role played by pulmonary endothelial cells as amplifiers of cytokine storm during influenza infection are described...
  36. pmc Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1
    Daniel A Bachovchin
    The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Med Chem 54:5229-36. 2011
    ....
  37. pmc Discovery, synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z,5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2-(alkylimino)thiazolidin-4-one chemotype
    Mariangela Urbano
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA
    Bioorg Med Chem Lett 21:6739-45. 2011
    ..The lead molecule herein disclosed constitutes a valuable pharmacological tool to explore the effects of the S1P(4)-R signaling cascade and elucidate the molecular basis of the receptor function...
  38. pmc Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy
    Kevin B Walsh
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, USA
    J Virol 88:6281-93. 2014
    ....
  39. pmc Mapping the innate signaling cascade essential for cytokine storm during influenza virus infection
    John R Teijaro
    Department of Immunology and Microbial Science, Department of Chemical Physiology, Skaggs Institute for Chemical Biology, and Scripps Research Institute Molecular Screening Center, The Scripps Research Institute, La Jolla, CA 92037
    Proc Natl Acad Sci U S A 111:3799-804. 2014
    ..We identify the MyD88 adaptor molecule as responsible for the majority of cytokine amplification observed following influenza virus challenge. ..
  40. ncbi request reprint Sphingosine 1-phosphate receptor agonists: a patent review (2010-2012)
    Edward Roberts
    The Scripps Research Institute, Department of Chemistry, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA
    Expert Opin Ther Pat 23:817-41. 2013
    ..In contrast to the S1P1-R, the therapeutic application of the S1P(2-5)-Rs remains poorly explored...
  41. doi request reprint Real-time differential labeling of blood, interstitium, and lymphatic and single-field analysis of vasculature dynamics in vivo
    Gor Sarkisyan
    Department of Chemical Physiology, The Scripps Research Institute, 10550 N Torrey Pines Rd MEM L55, La Jolla, CA 92037, USA
    Am J Physiol Cell Physiol 302:C1460-8. 2012
    ..Last, single-field fluid movement dynamics can be derived, allowing for the simultaneous determination of fluid flow rates in diverse blood and lymphatic compartments...
  42. doi request reprint Quelling the storm: utilization of sphingosine-1-phosphate receptor signaling to ameliorate influenza virus-induced cytokine storm
    Kevin B Walsh
    Department of Immunology and Microbial Science, The Scripps Research Institute, IMM 6, 10550 North Torrey Pines Rd, La Jolla, CA 92037, USA
    Immunol Res 51:15-25. 2011
    ....
  43. pmc Protection of ferrets from pulmonary injury due to H1N1 2009 influenza virus infection: immunopathology tractable by sphingosine-1-phosphate 1 receptor agonist therapy
    John R Teijaro
    Viral Immunobiology Laboratory, Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA Electronic address
    Virology 452:152-7. 2014
    ..S1P1R agonist was more effective in reducing pulmonary injury than the antiviral drug oseltamivir but, importantly, combined therapy was significantly more effective than either therapy alone. ..
  44. pmc The function of follicular helper T cells is regulated by the strength of T cell antigen receptor binding
    Nicolas Fazilleau
    Department of Immunology and Microbial Sciences, La Jolla, California, USA
    Nat Immunol 10:375-84. 2009
    ..Our studies demonstrate a central function for differences in the binding strength of the T cell antigen receptor in the antigen-specific mechanisms that 'program' specialized effector T(FH) function in vivo...
  45. pmc Discovery, design and synthesis of a selective S1P(3) receptor allosteric agonist
    Miguel Guerrero
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 23:6346-9. 2013
    ....
  46. pmc Discovery, design and synthesis of the first reported potent and selective sphingosine-1-phosphate 4 (S1P4) receptor antagonists
    Miguel Guerrero
    Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 21:3632-6. 2011
    ....
  47. pmc Suppression of cytokine storm with a sphingosine analog provides protection against pathogenic influenza virus
    Kevin B Walsh
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 108:12018-23. 2011
    ..With cytokine storm playing a role in the pathogenesis of a wide assortment of viral, bacterial, and immunologic diseases, a therapeutic approach using sphingosine analogs is of particular interest...
  48. pmc Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors
    Daniel A Bachovchin
    The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 108:6811-6. 2011
    ....
  49. ncbi request reprint Cytokine storm plays a direct role in the morbidity and mortality from influenza virus infection and is chemically treatable with a single sphingosine-1-phosphate agonist molecule
    Michael B A Oldstone
    Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA
    Curr Top Microbiol Immunol 378:129-47. 2014
    ..The mechanism(s) of how S1P1R signaling works and the pathways involved are subjects of this review. ..
  50. ncbi request reprint Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network
    Hugh Rosen
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Nat Rev Immunol 5:560-70. 2005
    ..S1P-S1P-receptor regulatory systems might therefore be novel targets for the therapy of diverse immunological diseases...
  51. doi request reprint Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation
    Frank Niessen
    Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA
    Nature 452:654-8. 2008
    ..Thus, activation of dendritic cells by coagulation in the lymphatics emerges as a previously unknown mechanism that promotes systemic inflammation and lethality in decompensated innate immune responses...
  52. ncbi request reprint CD8+ T cell tolerance in nonobese diabetic mice is restored by insulin-dependent diabetes resistance alleles
    Xavier Martinez
    Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA
    J Immunol 175:1677-85. 2005
    ..These results underscore the variety of ways that autoimmunity can be prevented and identify the elimination of islet-specific CD8+ T cells as a common indicator of high-level protection...
  53. pmc Oxime esters as selective, covalent inhibitors of the serine hydrolase retinoblastoma-binding protein 9 (RBBP9)
    Daniel A Bachovchin
    Department of Chemical Physiology, The Scripps Research Institute, 10550 N Torrey Pines Rd La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 20:2254-8. 2010
    ....
  54. doi request reprint A GTP affinity probe for proteomics highlights flexibility in purine nucleotide selectivity
    Elizabeth A George Cisar
    The Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Am Chem Soc 135:4676-9. 2013
    ..The GTP-BP-yne probe will be a useful tool for the study of GTP-binding proteins, especially when targets of interest are not known a priori...
  55. pmc A sphingosine 1-phosphate receptor 2 selective allosteric agonist
    Hideo Satsu
    Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1 1 1 Yayoi, Bunkyo ku, Tokyo 113 8657, Japan
    Bioorg Med Chem 21:5373-82. 2013
    ..Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with S1P is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. ..
  56. pmc Novel inhibitors for PRMT1 discovered by high-throughput screening using activity-based fluorescence polarization
    Myles B C Dillon
    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, United States
    ACS Chem Biol 7:1198-204. 2012
    ....
  57. pmc Modulation of chemokines and allergic airway inflammation by selective local sphingosine-1-phosphate receptor 1 agonism in lungs
    David Marsolais
    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California, USA
    Mol Pharmacol 79:61-8. 2011
    ..Specific S1P₁ agonism in lungs contributes significantly to anti-inflammatory activities of sphingosine-1-phosphate therapeutics by suppressing chemokine release in the airways, and may be of clinical relevance...
  58. ncbi request reprint Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases
    Jerold Chun
    Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Curr Pharm Des 12:161-71. 2006
    ..Here we provide a brief introduction to receptor-mediated lysophospholipid signaling and discuss its basic and potential therapeutic roles in autoimmune-related diseases...
  59. ncbi request reprint S1P1-selective agonist SEW2871 exacerbates reperfusion arrhythmias
    Yayoi T Tsukada
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, USA
    J Cardiovasc Pharmacol 50:660-9. 2007
    ..This is the first demonstration of the critical role of the S1P1 receptor in I/R injury...
  60. doi request reprint Chemical modulators of sphingosine-1-phosphate receptors as barrier-oriented therapeutic molecules
    David Marsolais
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    Nat Rev Drug Discov 8:297-307. 2009
    ..This Review discusses the role of sphingosine-1-phosphate receptors in the regulation and protection of biological barriers, and the potential of therapeutic strategies that target this receptor family...
  61. ncbi request reprint Antagonists of the kappa opioid receptor
    Mariangela Urbano
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 24:2021-32. 2014
    ..This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists...
  62. pmc Modulators of the Sphingosine 1-phosphate receptor 1
    Mariangela Urbano
    Department of Chemistry, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037, United States
    Bioorg Med Chem Lett 23:6377-89. 2013
    ..This review provides the latest advances on next-generation S1P1-R modulators from 2012 up to date, with an overview of the chemical structures, structure-activity relationships, and relevant biological and clinical properties. ..
  63. pmc The GPCR Network: a large-scale collaboration to determine human GPCR structure and function
    Raymond C Stevens
    Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, USA
    Nat Rev Drug Discov 12:25-34. 2013
    ....
  64. pmc High-throughput screening for inhibitors of sialyl- and fucosyltransferases
    Cory D Rillahan
    Department of Chemical Physiology, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA
    Angew Chem Int Ed Engl 50:12534-7. 2011
    ..The screening of 16,000 compounds against different glycosyltransferases has identified various interesting inhibitors...
  65. pmc Ranking the selectivity of PubChem screening hits by activity-based protein profiling: MMP13 as a case study
    Ryuichiro Nakai
    Department of Chemical Physiology, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Bioorg Med Chem 17:1101-8. 2009
    ..We anticipate that ABPP will find general utility as a platform to rank the selectivity of lead compounds emerging from HTS assays for a wide variety of enzymes...
  66. pmc A fluorescent plate reader assay for ceramide kinase
    Anthony S Don
    Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA 92037, USA
    Anal Biochem 375:265-71. 2008
    ....
  67. ncbi request reprint Application of beta-lactamase enzyme complementation to the high-throughput screening of toll-like receptor signaling inhibitors
    Hyun Ku Lee
    Department of Immunology, IMM 12, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Mol Pharmacol 72:868-75. 2007
    ..7 cells. One compound is effective near 100 nM. None of the compounds showed any cytotoxicity at 20 microM...
  68. doi request reprint A high-throughput cell-based Gaussia luciferase reporter assay for identifying modulators of fibulin-3 secretion
    John D Hulleman
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA
    J Biomol Screen 18:647-58. 2013
    ..The identified compounds could serve as tools for probing the etiology of fibulin-3-related diseases. ..
  69. pmc Identification of selective inhibitors of uncharacterized enzymes by high-throughput screening with fluorescent activity-based probes
    Daniel A Bachovchin
    The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA
    Nat Biotechnol 27:387-94. 2009
    ..Furthermore, we show that the detoxification enzyme GSTO1, also implicated in cancer, is inhibited by several electrophilic compounds found in public libraries, some of which display high selectivity for this protein...
  70. pmc A novel and specific NADPH oxidase-1 (Nox1) small-molecule inhibitor blocks the formation of functional invadopodia in human colon cancer cells
    Davide Gianni
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California 92037, USA
    ACS Chem Biol 5:981-93. 2010
    ..These results elucidate the relevance of Nox1-dependent ROS generation in mechanisms of cancer invasion and define ML171 as a useful Nox1 chemical probe and potential therapeutic agent for inhibition of cancer cell invasion...
  71. ncbi request reprint Sphingosine-1-phosphate receptor agonism impairs the efficiency of the local immune response by altering trafficking of naive and antigen-activated CD4+ T cells
    Jenny H Xie
    Department of Pharmacology, Merck Research Laboratories, Rahway NJ 07065, USA
    J Immunol 170:3662-70. 2003
    ..Thus, FTY720 induces immunosuppression through inhibition of both the recirculation of naive T cells and the release of Ag-activated T cells from the DLN to lymph and to the blood compartment...
  72. ncbi request reprint Potent S1P receptor agonists replicate the pharmacologic actions of the novel immune modulator FTY720
    Jeffrey J Hale
    Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 14:3351-5. 2004
    ..The similar S1P receptor profiles of 2 and 19 coupled with their comparable potency in vivo supports a connection between S1P receptor agonism and immunosuppressive efficacy...
  73. ncbi request reprint The discovery of 3-(N-alkyl)aminopropylphosphonic acids as potent S1P receptor agonists
    Jeffrey J Hale
    Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 14:3495-9. 2004
    ..3-(N-Alkyl)aminopropylphosphonic acids are potent agonists of four of the five known sphingosine-1-phosphate (S1P) receptor subtypes...
  74. pmc Regulation of immunity by lysosphingolipids and their G protein-coupled receptors
    Edward J Goetzl
    Department of Medicine, UCSF, San Francisco, California, USA
    J Clin Invest 114:1531-7. 2004
    ....
  75. ncbi request reprint A rational utilization of high-throughput screening affords selective, orally bioavailable 1-benzyl-3-carboxyazetidine sphingosine-1-phosphate-1 receptor agonists
    Jeffrey J Hale
    Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    J Med Chem 47:6662-5. 2004
    ..Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey...
  76. ncbi request reprint Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists
    Jeffrey J Hale
    Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 14:3501-5. 2004
    ....
  77. ncbi request reprint Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses
    Sindy H Wei
    Department of Physiology and Biophysics and Center for Immunology, University of California, Irvine, California 92697 4561, USA
    Nat Immunol 6:1228-35. 2005
    ..Our results provide visualization of transendothelial migration of T cells into lymphatic sinuses and suggest that S1P(1) agonists act mainly on endothelial cell S1P(1) receptors to inhibit lymphocyte migration...
  78. ncbi request reprint Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists
    Suzanne Mandala
    Department of Immunology and Rheumatology, Merck Research Laboratories, Post Office Box 2000, Rahway, NJ 07065, USA
    Science 296:346-9. 2002
    ..Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression...
  79. ncbi request reprint Design and synthesis of conformationally constrained 3-(N-alkylamino)propylphosphonic acids as potent agonists of sphingosine-1-phosphate (S1P) receptors
    Lin Yan
    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
    Bioorg Med Chem Lett 14:4861-6. 2004
    ....
  80. ncbi request reprint Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3
    Zhen Li
    Department of Medicinal Chemistry, Merck Research Laboratory, Rahway, New Jersey 07065, USA
    J Med Chem 48:6169-73. 2005
    ..Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy...
  81. ncbi request reprint A fully automated [35S]GTPgammaS scintillation proximity assay for the high-throughput screening of Gi-linked G protein-coupled receptors
    Marc Ferrer
    Department of Automated Biotechnology, Merck Research Laboratories, North Wales, Pennsylvania, USA
    Assay Drug Dev Technol 1:261-73. 2003
    ..Here we compare [(35)S]GTPgammaS scintillation proximity binding assays for two different G(i)-coupled GPCRs, and describe their implementation with automated high-throughput systems...
  82. ncbi request reprint Molecular characterization of the murine SIGNR1 gene encoding a C-type lectin homologous to human DC-SIGN and DC-SIGNR
    Stephen A Parent
    Department of Immunology and Rheumatology, Merck Research Laboratories, PO Box 2000, RY 80Y 225, Rahway, NJ 07065, USA
    Gene 293:33-46. 2002
    ..In situ hybridization and immunocytochemistry experiments demonstrate that, like human DC-SIGN, the murine messenger RNAs are expressed in subsets of dendritic cells in the spleen and skin...

Research Grants8

  1. S1P Receptor subtypes: Regulating lymphocyte trafficking
    Hugh Rosen; Fiscal Year: 2005
    ..These studies will yield an enhanced understanding of the basic mechanisms by which S1P receptor agonism induces clinically useful immunosuppression of potential use in autoimmunity. ..
  2. S1P Receptor subtypes: Regulating lymphocyte trafficking
    Hugh Rosen; Fiscal Year: 2007
    ..These studies will yield an enhanced understanding of the basic mechanisms by which S1P receptor agonism induces clinically useful immunosuppression of potential use in autoimmunity. ..
  3. S1P Receptor subtypes: Regulating lymphocyte trafficking
    Hugh Rosen; Fiscal Year: 2004
    ..These studies will yield an enhanced understanding of the basic mechanisms by which S1P receptor agonism induces clinically useful immunosuppression of potential use in autoimmunity. ..
  4. S1P Receptor subtypes: Regulating lymphocyte trafficking
    Hugh Rosen; Fiscal Year: 2006
    ..These studies will yield an enhanced understanding of the basic mechanisms by which S1P receptor agonism induces clinically useful immunosuppression of potential use in autoimmunity. ..
  5. Molecular Libraries Screening Centers Network (MLSCN)(RMI)
    Hugh Rosen; Fiscal Year: 2007
    ....
  6. Molecular Libraries Screening Centers Network (MLSCN)(RMI)
    Hugh Rosen; Fiscal Year: 2007
    ....