Selective Glucocorticoid Receptor modulators.

The ancient two-faced Roman god Janus is often used as a metaphor to describe the characteristics of the Glucocorticoid Receptor (NR3C1), which exhibits both a beneficial side, that serves to halt inflammation, and a detrimental side responsible for undesirable effects. However, recent developments suggest that the Glucocorticoid Receptor has many more faces with the potential to express a range of different functionalities, depending on factors that include the tissue type, ligand type, receptor variants, cofactor surroundings and target gene promoters. This behavior of the receptor has made the development of safer ligands, that trigger the expression program of only a desirable subset of genes, a real challenge. Thus more knowledge-based fundamental research is needed to ensure the design and development of selective Glucocorticoid Receptor modulators capable of reaching the clinic. Recent advances in the characterization of novel selective Glucocorticoid Receptor modulators, specifically in the context of anti-inflammatory strategies, will be described in this review.

[1]  G. Haegeman,et al.  Glucocorticoids and mitogen- and stress-activated protein kinase 1 inhibitors: possible partners in the combat against inflammation. , 2009, Biochemical pharmacology.

[2]  K. Asadullah,et al.  Characterization of ZK 245186, a novel, selective glucocorticoid receptor agonist for the topical treatment of inflammatory skin diseases , 2009, British journal of pharmacology.

[3]  K. Kaestner,et al.  DNA Binding of the Glucocorticoid Receptor Is Not Essential for Survival , 1998, Cell.

[4]  A. Borisy,et al.  Selective amplification of glucocorticoid anti-inflammatory activity through synergistic multi-target action of a combination drug , 2009, Arthritis research & therapy.

[5]  J. Tuckermann,et al.  Therapeutic and Adverse Effects of a Non-Steroidal Glucocorticoid Receptor Ligand in a Mouse Model of Multiple Sclerosis , 2009, PloS one.

[6]  H. T. Jones,et al.  Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity. , 2007, Journal of medicinal chemistry.

[7]  T. Scanlan,et al.  Design and evaluation of novel nonsteroidal dissociating glucocorticoid receptor ligands. , 2004, Bioorganic & medicinal chemistry letters.

[8]  M. Nakane,et al.  A novel antiinflammatory maintains glucocorticoid efficacy with reduced side effects. , 2003, Molecular endocrinology.

[9]  T. Kino,et al.  Circadian rhythm transcription factor CLOCK regulates the transcriptional activity of the glucocorticoid receptor by acetylating its hinge region lysine cluster: potential physiological implications , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  K. Yamamoto,et al.  The Ligand Binding Domain Controls Glucocorticoid Receptor Dynamics Independent of Ligand Release , 2007, Molecular and Cellular Biology.

[11]  J. Lehár,et al.  Synergistic drug combinations improve therapeutic selectivity , 2009, Nature Biotechnology.

[12]  A. Papadimitriou,et al.  Regulation of the Hypothalamic-Pituitary-Adrenal Axis , 2009, Neuroimmunomodulation.

[13]  K. Yamamoto,et al.  DNA Binding Site Sequence Directs Glucocorticoid Receptor Structure and Activity , 2009, Science.

[14]  H. T. Jones,et al.  Non-steroidal glucocorticoid agonists: the discovery of aryl pyrazoles as A-ring mimetics. , 2007, Bioorganic & medicinal chemistry letters.

[15]  H. Gronemeyer,et al.  Synthetic glucocorticoids that dissociate transactivation and AP-1 transrepression exhibit antiinflammatory activity in vivo. , 1997, Molecular Endocrinology.

[16]  D. Hommes,et al.  Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists , 2007, Molecular and Cellular Endocrinology.

[17]  Novel heterocyclic glucocorticoids: in vitro profile and in vivo efficacy. , 2005, Bioorganic & medicinal chemistry letters.

[18]  D. DeFranco,et al.  Bidirectional transport of glucocorticoid receptors across the nuclear envelope. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[19]  K. Asadullah,et al.  Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  C. Battram,et al.  Therapeutic Benefit of a Dissociated Glucocorticoid and the Relevance of In Vitro Separation of Transrepression from Transactivation Activity , 2001, The Journal of Immunology.

[21]  K. Yamamoto,et al.  Factor recruitment and TIF2/GRIP1 corepressor activity at a collagenase‐3 response element that mediates regulation by phorbol esters and hormones , 2001, The EMBO journal.

[22]  P. Meltzer,et al.  Kinetic complexity of the global response to glucocorticoid receptor action. , 2009, Endocrinology.

[23]  C. Glass,et al.  Coregulator Codes of Transcriptional Regulation by Nuclear Receptors* , 2001, The Journal of Biological Chemistry.

[24]  Marc Montminy,et al.  CREB regulates hepatic gluconeogenesis through the coactivator PGC-1 , 2001, Nature.

[25]  H. Schluesener,et al.  Compound A, a Plant Origin Ligand of Glucocorticoid Receptors, Increases Regulatory T Cells and M2 Macrophages to Attenuate Experimental Autoimmune Neuritis with Reduced Side Effects , 2009, The Journal of Immunology.

[26]  C. Farquharson,et al.  The growth plate sparing effects of the selective glucocorticoid receptor modulator, AL-438 , 2007, Molecular and Cellular Endocrinology.

[27]  Khusru Asadullah,et al.  Insight into the molecular mechanisms of glucocorticoid receptor action promotes identification of novel ligands with an improved therapeutic index , 2006, Experimental dermatology.

[28]  Raj Kumar,et al.  Gene regulation by the glucocorticoid receptor: Structure:function relationship , 2005, The Journal of Steroid Biochemistry and Molecular Biology.

[29]  K. Yamamoto,et al.  Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  P. Chambon,et al.  Crystal structure of a heterodimeric complex of RAR and RXR ligand-binding domains. , 2000, Molecular cell.

[31]  J. Cidlowski,et al.  Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification , 2006, The Journal of Steroid Biochemistry and Molecular Biology.

[32]  Guillaume Adelmant,et al.  Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 , 2001, Nature.

[33]  T. Willson,et al.  Crystal Structure of the Glucocorticoid Receptor Ligand Binding Domain Reveals a Novel Mode of Receptor Dimerization and Coactivator Recognition , 2002, Cell.

[34]  I. McLay,et al.  Design and x-ray crystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor , 2009, Proceedings of the National Academy of Sciences.

[35]  Khusru Asadullah,et al.  Mechanisms involved in the side effects of glucocorticoids. , 2002, Pharmacology & therapeutics.

[36]  G. Haegeman,et al.  Antiinflammatory properties of a plant-derived nonsteroidal, dissociated glucocorticoid receptor modulator in experimental autoimmune encephalomyelitis. , 2010, Molecular endocrinology.

[37]  W. Pratt,et al.  Regulation of Signaling Protein Function and Trafficking by the hsp90/hsp70-Based Chaperone Machinery 1 , 2003, Experimental biology and medicine.

[38]  F. Holsboer,et al.  The activated glucocorticoid receptor inhibits the transcription factor T‐bet by direct protein‐protein interaction , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[39]  G. Chrousos,et al.  Glucocorticoid Receptor Mutants Demonstrate Increased Motility Inside the Nucleus of Living Cells: Time of Fluorescence Recovery After Photobleaching (FRAP) Is an Integrated Measure of Receptor Function , 2004, Molecular medicine.

[40]  Florian Holsboer,et al.  Glucocorticoids inhibitGATA‐3 phosphorylation and activity in T cells , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[41]  K. H. Richter,et al.  The DNA Binding-Independent Function of the Glucocorticoid Receptor Mediates Repression of Ap-1–Dependent Genes in Skin , 1999, The Journal of cell biology.

[42]  S. van Calenbergh,et al.  Differential mechanism of NF-kappaB inhibition by two glucocorticoid receptor modulators in rheumatoid arthritis synovial fibroblasts. , 2009, Arthritis and rheumatism.

[43]  J. Glyn.  The discovery and early use of cortisone , 1998, Journal of the Royal Society of Medicine.

[44]  K. Yamamoto,et al.  Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity. , 2006, Genes & development.

[45]  E. Arzt,et al.  Glucocorticoids in the regulation of transcription factors that control cytokine synthesis. , 2007, Cytokine & growth factor reviews.

[46]  W. Gong,et al.  Analysis of the Dissociated Steroid RU24858 Does Not Exclude a Role for Inducible Genes in the Anti-Inflammatory Actions of Glucocorticoids , 2006, Molecular Pharmacology.

[47]  J. Gustafsson,et al.  Characterization of a steroid hormone receptor gene and mRNA in wild-type and mutant cells , 1984, Nature.

[48]  Richard M Myers,et al.  Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation. , 2009, Genome research.

[49]  I. Adcock,et al.  The glucocorticoid RU24858 does not distinguish between transrepression and transactivation in primary human eosinophils , 2006, Journal of Inflammation.

[50]  E. Laird,et al.  Octahydrophenanthrene-2,7-diol analogues as dissociated glucocorticoid receptor agonists: discovery and lead exploration. , 2009, Journal of medicinal chemistry.

[51]  D. Edwards,et al.  Lactogenic Hormonal Induction of Long Distance Interactions between β-Casein Gene Regulatory Elements* , 2009, The Journal of Biological Chemistry.

[52]  G. Hager,et al.  Dynamic access of the glucocorticoid receptor to response elements in chromatin. , 2009, The international journal of biochemistry & cell biology.

[53]  P. Chambon,et al.  Crystal structure of the RAR-gamma ligand-binding domain bound to all-trans retinoic acid. , 1995, Nature.

[54]  G. Haegeman,et al.  Dissociated glucocorticoids with anti-inflammatory potential repress interleukin-6 gene expression by a nuclear factor-kappaB-dependent mechanism. , 1999, Molecular pharmacology.

[55]  A. Hoffmann,et al.  Molecular Determinants of Crosstalk between Nuclear Receptors and Toll-like Receptors , 2005, Cell.

[56]  O. Meijer,et al.  Homodimerization of the glucocorticoid receptor is not essential for response element binding: activation of the phenylethanolamine N-methyltransferase gene by dimerization-defective mutants. , 2003, Molecular endocrinology.

[57]  J. Pfeilschifter,et al.  Dissociated glucocorticoids equipotently inhibit cytokine- and cAMP-induced matrix degrading proteases in rat mesangial cells. , 2005, Biochemical pharmacology.

[58]  P. Herrlich,et al.  Repression of inflammatory responses in the absence of DNA binding by the glucocorticoid receptor , 2001, The EMBO journal.

[59]  K. Ikizawa,et al.  In vivo analysis of glucocorticoid-induced reporter gene expression using gene gun DNA delivery. , 2002, Biological & pharmaceutical bulletin.

[60]  R. Evans,et al.  Primary structure and expression of a functional human glucocorticoid receptor cDNA , 1985, Nature.

[61]  Dale E Mais,et al.  Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma. , 2007, Journal of medicinal chemistry.

[62]  G. Haegeman,et al.  A fully dissociated compound of plant origin for inflammatory gene repression. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[63]  J. Williams,et al.  Effects of dissociated glucocorticoids on OPG and RANKL in osteoblastic cells. , 2006, Bone.

[64]  R. Chatterton,et al.  Novel steroid receptor phyto-modulator compound a inhibits growth and survival of prostate cancer cells. , 2008, Cancer research.

[65]  P. Swart,et al.  Biological activities of the shrub Salsola tuberculatiformis Botsch.: contraceptive or stress alleviator? , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[66]  K. Asadullah,et al.  Selective glucocorticoid receptor agonists (SEGRAs): Novel ligands with an improved therapeutic index , 2007, Molecular and Cellular Endocrinology.

[67]  D. Figarella-Branger,et al.  Role of Brg1 and HDAC2 in GR trans-repression of the pituitary POMC gene and misexpression in Cushing disease. , 2006, Genes & development.

[68]  M. Garabedian,et al.  Modulation of glucocorticoid receptor phosphorylation and transcriptional activity by a C-terminal-associated protein phosphatase. , 2007, Molecular endocrinology.

[69]  J. Philippé,et al.  Hop bitter acids efficiently block inflammation independent of GRalpha, PPARalpha, or PPARgamma. , 2009, Molecular nutrition & food research.

[70]  D. Zaller,et al.  Novel glucocorticoids containing a 6,5-bicyclic core fused to a pyrazole ring: synthesis, in vitro profile, molecular modeling studies, and in vivo experiments. , 2007, Bioorganic & medicinal chemistry letters.

[71]  B. Groner,et al.  Regulation of the trans-activation potential of STAT5 through its DNA-binding activity and interactions with heterologous transcription factors. , 2000, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[72]  O. Meijer,et al.  MicroRNA 18 and 124a down-regulate the glucocorticoid receptor: implications for glucocorticoid responsiveness in the brain. , 2009, Endocrinology.

[73]  G. Haegeman,et al.  PPARα blocks glucocorticoid receptor α-mediated transactivation but cooperates with the activated glucocorticoid receptor α for transrepression on NF-κB , 2009, Proceedings of the National Academy of Sciences.

[74]  Ting-Chao Chou,et al.  Theoretical Basis, Experimental Design, and Computerized Simulation of Synergism and Antagonism in Drug Combination Studies , 2006, Pharmacological Reviews.

[75]  M. D. Leibowitz,et al.  LGD-5552, an antiinflammatory glucocorticoid receptor ligand with reduced side effects, in vivo. , 2008, Endocrinology.

[76]  C. Glass,et al.  Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response. , 2006, Genes & development.

[77]  T. Scanlan,et al.  Differential In Vivo Effects on Target Pathways of a Novel Arylpyrazole Glucocorticoid Receptor Modulator Compared with Prednisolone , 2010, Journal of Pharmacology and Experimental Therapeutics.

[78]  K. Yamamoto,et al.  Crosstalk in inflammation: the interplay of glucocorticoid receptor-based mechanisms and kinases and phosphatases. , 2009, Endocrine reviews.

[79]  W. V. Berghe,et al.  Abrogation of Glucocorticoid Receptor Dimerization Correlates with Dissociated Glucocorticoid Behavior of Compound A* , 2009, The Journal of Biological Chemistry.

[80]  S. van Calenbergh,et al.  A Plant-Derived Ligand Favoring Monomeric Glucocorticoid Receptor Conformation with Impaired Transactivation Potential Attenuates Collagen-Induced Arthritis1 , 2008, The Journal of Immunology.

[81]  J. Collins,et al.  Selective Regulation of Bone Cell Apoptosis by Translational Isoforms of the Glucocorticoid Receptor , 2007, Molecular and Cellular Biology.

[82]  J. Proudfoot,et al.  Identification of dissociated non-steroidal glucocorticoid receptor agonists. , 2007, Bioorganic & medicinal chemistry letters.