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This version published online on March 13, 2007
Molecular Endocrinology, doi:10.1210/me.2006-0524
A more recent version of this article appeared on May 1, 2007
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Submitted on December 6, 2006
Accepted on March 5, 2007

A Structural and in vitro Characterization of Asoprisnil: a Selective Progesterone Receptor Modulator

Kevin P. Madauss, Eugene T. Grygielko, Su-Jun Deng, Anthony C. Sulpizio, Thomas B. Stanley, Charlene Wu, Steve A. Short, Scott K. Thompson, Eugene L. Stewart, Nicholas J. Laping, Shawn P. Williams, and Jeffrey D. Bray*

Departments of Computational, Analytical and Structural Sciences (K.P.M., E.L.S., S.P.W.), and Gene Expression and Protein Biochemistry (S-J. D., T.B.S., S.A.S.) GlaxoSmithKline Discovery Research, Research Triangle Park, NC 27709, USA. Departments of Urogenital Biology (E.T.G., A.C.S., C.W., N.J.L., J.D.B.) and Medicinal Chemistry (S.K.T.), GlaxoSmithKline Cardiovascular and Urogenital Center for Excellence in Drug Discovery, King of Prussia, PA 19406, USA

* To whom correspondence should be addressed. E-mail: jeffrey.d.bray{at}gsk.com.

Selective Progesterone Receptor Modulators (SPRMs) have been suggested as therapeutic agents for treatment of gynecological disorders. One such SPRM, Asoprisnil, was recently in clinical trials for treatment of uterine fibroids and endometriosis. We present the crystal structures of Progesterone Receptor (PR) ligand binding domain complexed with Asoprisnil and the co-repressors NCoR and SMRT. This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors. These structures show PR in a different conformation than PR complexed with Progesterone (P4). We profiled Asoprisnil in PR-dependent assays to further understand the PR-mediated mechanism of action. We confirmed previous findings that Asoprisnil demonstrated antagonism, but not agonism, in a PR-B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay. Asoprisnil, but not RU486, weakly recruited the coactivators SRC-1 and AIB1. However, Asoprisnil strongly recruited the corepressor NCoR in manner similar to RU486. Unlike RU486, NCoR binding to Asoprisnil-bound PR could be displaced with equal affinity by NCoR or TIF2 peptides. We further showed that it weakly activated T47D cell gene expression of Sgk-1 and PPL, and antagonized P4-induced expression of both genes. In rat leiomyoma ELT3 cells, Asoprisnil demonstrated partial P4-like inhibition of cyclooxygenase (COX) enzymatic activity and COX-2 gene expression. In the rat uterotrophic assay, Asoprisnil demonstrated no P4-like ability to oppose estrogen. Our data suggest that Asoprisnil differentially recruits coactivators and corepressors compared to RU486 or P4, and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus.
Key words: Asoprisnil • progesterone receptor • crystallography • corepressor • coactivator

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PR
Coregulators:   SRC-1  |  GRIP1  |  AIB1  |  NCOR  |  SMRT
Ligands:   GW6471  |  17β-Estradiol  |  Progesterone  |  Mifepristone



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