| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Abbott Laboratories (M.J.C., P.B.J., B.L., M.N., C.W.L., S.W.E., P.R.K., J.R.L., G.W.C.), Abbott Park, Illinois 60064; Ligand Pharmaceuticals, Inc. (C.M.T., J.H., M.E., J.R., J.N.M.), San Diego, California 92121; and Mayo Clinic (R.T.), Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Jeffrey N. Miner, Department of Molecular and Cellular Biology, Ligand Pharmaceuticals, Inc., 10275 Science Center Drive, San Diego, California 92121. E-mail: jminer{at}ligand.com.
Glucocorticoids (GCs) are commonly used to treat inflammatory disease; unfortunately, the long-term use of these steroids leads to a large number of debilitating side effects. The antiinflammatory effects of GCs are a result of GC receptor (GR)-mediated inhibition of expression of proinflammatory genes as well as GR-mediated activation of antiinflammatory genes. Similarly, side effects are most likely due to both activated and repressed GR target genes in affected tissues. An as yet unachieved pharmaceutical goal is the development of a compound capable of separating detrimental side effects from antiinflammatory activity. We describe the discovery and characterization of AL-438, a GR ligand that exhibits an altered gene regulation profile, able to repress and activate only a subset of the genes normally regulated by GCs. When tested in vivo, AL-438 retains full antiinflammatory efficacy and potency comparable to steroids but its negative effects on bone metabolism and glucose control are reduced at equivalently antiinflammatory doses. The mechanism underlying this selective in vitro and in vivo activity may be the result of differential cofactor recruitment in response to ligand. AL-438 reduces the interaction between GR and peroxisomal proliferator-activated receptor 
coactivator-1, a cofactor critical for steroid-mediated glucose up-regulation, while maintaining normal interactions with GR-interacting protein 1. This compound serves as a prototype for a unique, nonsteroidal alternative to conventional GCs in treating inflammatory disease.
NURSA Molecule Pages Link:
This article has been cited by other articles:
 |
|
 |
|
  L. C. Hofbauer and M. Rauner Minireview: Live and Let Die: Molecular Effects of Glucocorticoids on Bone Cells Mol. Endocrinol., October 1, 2009; 23(10): 1525 - 1531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. De Bosscher and G. Haegeman Minireview: Latest Perspectives on Antiinflammatory Actions of Glucocorticoids Mol. Endocrinol., March 1, 2009; 23(3): 281 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. J. Lopez, R. J. Ardecky, B. Bebo, K. Benbatoul, L. De Grandpre, S. Liu, M. D. Leibowitz, K. Marschke, J. Rosen, D. Rungta, et al. LGD-5552, an Antiinflammatory Glucocorticoid Receptor Ligand with Reduced Side Effects, in Vivo Endocrinology, May 1, 2008; 149(5): 2080 - 2089. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Suino-Powell, Y. Xu, C. Zhang, Y.-g. Tao, W. D. Tolbert, S. S. Simons Jr., and H. E. Xu Doubling the Size of the Glucocorticoid Receptor Ligand Binding Pocket by Deacylcortivazol Mol. Cell. Biol., March 15, 2008; 28(6): 1915 - 1923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Dewint, V. Gossye, K. De Bosscher, W. Vanden Berghe, K. Van Beneden, D. Deforce, S. Van Calenbergh, U. Muller-Ladner, B. Vander Cruyssen, G. Verbruggen, et al. A Plant-Derived Ligand Favoring Monomeric Glucocorticoid Receptor Conformation with Impaired Transactivation Potential Attenuates Collagen-Induced Arthritis J. Immunol., February 15, 2008; 180(4): 2608 - 2615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Miner, B. Ardecky, K. Benbatoul, K. Griffiths, C. J. Larson, D. E. Mais, K. Marschke, J. Rosen, E. Vajda, L. Zhi, et al. Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein protein interaction profile PNAS, December 4, 2007; 104(49): 19244 - 19249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Newton and N. S. Holden Separating Transrepression and Transactivation: A Distressing Divorce for the Glucocorticoid Receptor? Mol. Pharmacol., October 1, 2007; 72(4): 799 - 809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kressler, M. B. Hock, and A. Kralli Coactivators PGC-1beta and SRC-1 Interact Functionally to Promote the Agonist Activity of the Selective Estrogen Receptor Modulator Tamoxifen J. Biol. Chem., September 14, 2007; 282(37): 26897 - 26907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. McMaster and D. W. Ray Modelling the glucocorticoid receptor and producing therapeutic agents with anti-inflammatory effects but reduced side-effects Exp Physiol, March 1, 2007; 92(2): 299 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. N. Miner, W. Chang, M. S. Chapman, P. D. Finn, M. H. Hong, F. J. Lopez, K. B. Marschke, J. Rosen, W. Schrader, R. Turner, et al. An Orally Active Selective Androgen Receptor Modulator Is Efficacious on Bone, Muscle, and Sex Function with Reduced Impact on Prostate Endocrinology, January 1, 2007; 148(1): 363 - 373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Rhee, H. Ge, W. Yang, M. Fan, C. Handschin, M. Cooper, J. Lin, C. Li, and B. M. Spiegelman Partnership of PGC-1{alpha} and HNF4{alpha} in the Regulation of Lipoprotein Metabolism J. Biol. Chem., May 26, 2006; 281(21): 14683 - 14690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. De Bosscher, W. V. Berghe, I. M. E. Beck, W. Van Molle, N. Hennuyer, J. Hapgood, C. Libert, B. Staels, A. Louw, and G. Haegeman A fully dissociated compound of plant origin for inflammatory gene repression PNAS, November 1, 2005; 102(44): 15827 - 15832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Rosen and J. N. Miner The Search for Safer Glucocorticoid Receptor Ligands Endocr. Rev., May 1, 2005; 26(3): 452 - 464. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Chadwick, S. Chippari, E. Matelan, L. Borges-Marcucci, A. M. Eckert, J. C. Keith Jr., L. M. Albert, Y. Leathurby, H. A. Harris, R. A. Bhat, et al. Identification of pathway-selective estrogen receptor ligands that inhibit NF-{kappa}B transcriptional activity PNAS, February 15, 2005; 102(7): 2543 - 2548. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Biggadike, I. Uings, and S. N. Farrow Designing Corticosteroid Drugs for Pulmonary Selectivity Proceedings of the ATS, December 1, 2004; 1(4): 352 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hochhaus New Developments in Corticosteroids Proceedings of the ATS, November 1, 2004; 1(3): 269 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Smith and B. W. O'Malley Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators Endocr. Rev., February 1, 2004; 25(1): 45 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Schacke, A. Schottelius, W.-D. Docke, P. Strehlke, S. Jaroch, N. Schmees, H. Rehwinkel, H. Hennekes, and K. Asadullah Dissociation of transactivation from transrepression by a selective glucocorticoid receptor agonist leads to separation of therapeutic effects from side effects PNAS, January 6, 2004; 101(1): 227 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Li, S. Wang, and T. D. Gelehrter Identification of Glucocorticoid Receptor Domains Involved in Transrepression of Transforming Growth Factor-{beta} Action J. Biol. Chem., October 24, 2003; 278(43): 41779 - 41788. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. De Bosscher, W. Vanden Berghe, and G. Haegeman The Interplay between the Glucocorticoid Receptor and Nuclear Factor-{kappa}B or Activator Protein-1: Molecular Mechanisms for Gene Repression Endocr. Rev., August 1, 2003; 24(4): 488 - 522. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
