Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile

doi:10.1073/pnas.0705517104

Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein–protein interaction profile

Discovery Research, Ligand Pharmaceuticals, San Diego, CA 92121

Edited by Keith R. Yamamoto, University of California, San Francisco, CA, and approved October 9, 2007 (received for review June 13, 2007)

Abstract

Glucocorticoids are commonly used antiinflammatory agents whose use is limited by side effects. We have developed a series of glucocorticoid receptor (GR) ligands that retain the strong antiinflammatory activity of conventional glucocorticoids with reduced side effects. We present a compound, LGD5552, that binds the receptor efficiently and strongly represses inflammatory gene expression. LGD5552 bound to GR activates gene expression somewhat differently than glucocorticoids. It activates some genes with an efficacy similar to that of the glucocorticoids. However, other glucocorticoid-activated genes are not regulated by LGD5552. These differences may be because of the more efficient binding of corepressor in the presence of LGD5552, compared with glucocorticoid agonists. This class of nonsteroidal, GR-dependent antiinflammatory drugs may offer a safer alternative to steroidal glucocorticoids in the treatment of inflammatory disease.

Footnotes

*To whom correspondence should be addressed. E-mail: jminer{at}ligand.com
Author contributions: J.N.M., B.A., C.J.L., K.M., J.R., E.V., and A.N.-V. designed research; B.A., K.B., K.G., C.J.L., D.E.M., and E.V. performed research; L.Z. contributed new reagents/analytic tools; J.N.M., K.B., K.G., D.E.M., K.M., and J.R. analyzed data; and J.N.M. wrote the paper.
↵ ^†Present address: Tanabe Research Laboratories, 4540 Towne Centre Court, San Diego, CA 92121.
↵ ^‡Present address: Pfizer, 10646 Science Center Drive (CB3), San Diego, CA 92121.
↵ ^§Present address: Kemia, 5871 Oberlin Drive, Suite 100, San Diego, CA 92121.
↵ ^¶Present address: Exelixis, 4757 Nexus Centre Drive, San Diego, CA 92121.
Conflict of interest statement: The authors are or were employed by Ligand Pharmaceuticals.
This article is a PNAS Direct Submission.