Summary of the probe development efforts to identify novel inverse agonists of the liver receptor homolog-1 (LRH1; NR5A2)
Name: Summary of the probe development efforts to identify novel inverse agonists of the liver receptor homolog-1 (LRH1; NR5A2). ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRISMC)
Center Affiliation: The Scripps Research Institute, TSRI
Assay Provider: Patrick Griffin, TSRI
Network: Molecular Library Probe Production Center Network (MLPCN)
Grant Proposal Number: U54 MH084512
Grant Proposal PI: Patrick Griffin, TSRI
External Assay ID: LRH1_INH_SUMMARY (inverse agonists)
Name: Summary of the probe development efforts to identify novel inverse agonists of the liver receptor homolog-1 (LRH1; NR5A2).
NR5A2 or Liver receptor homologue-1 (LRH1) is a member of the NR5A, or Ftz-F1, subfamily V nuclear receptors for which there are four members (1). Murine LRH1 was originally identified due to its sequence homology to the Drosophila Fushi tarazu factor-1 but orthologs have been subsequently identified in several other species including rat, chicken, horse, zebrafish and human (2-7). LRH1, and its closest family member steroidogenic factor-1 (SF-1, NR5A1), bind to identical DNA consensus sequences (response elements or REs) and both have the ability to bind phospholipids in their ligand binding domains (LBDs) (8-10). However, LRH1 and SF-1 are expressed in different tissues and thus are considered likely to have non-overlapping, non-redundant functions. SF-1 expression is confined to steroidogenic tissues and adrenals where it regulates development, differentiation, steroidogenesis and sexual determination (5, 7, 11). LRH1 is highly expressed in tissues of endodermal origin and its expression is essential for normal liver, intestine, and pancreas function. LRH1 has also been shown to be expressed in the ovary and adipose tissue.
In a very recent report, Chand and colleagues investigated the mechanism of action of LRH1 in invasive breast cancer cells. They found that LRH1 promotes motility and cell invasiveness in both ER-positive (MCF-7) and ER-negative (MDA-MB-231) breast cancer cells and similar effects were observed in non-tumorigenic mammary epithelial cells. Interestingly, both remodeling of the actin cytoskeleton and E-cadherin processing were observed when LRH1 was over-expressed. These findings implicate LRH1 in promotion of migration and invasion in breast cancer independent of estrogen sensitivity. Together these findings provided strong evidence that LRH1 plays a significant role in tumor formation both in vitro and in vivo. Therefore, the identification of potent and selective LRH1 inverse agonists may provide new approaches for the treatment of cancer (12).
1. Fayard, E., J. Auwerx, and K. Schoonjans, LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis. Trends in Cell Biology, 2004. 14(5): p. 250-260.
2. Galarneau, L., J.F. Pare, D. Allard, D. Hamel, L. Levesque, J.D. Tugwood, S. Green, and L. Belanger, The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family. Mol Cell Biol, 1996. 16(7): p. 3853-65.
3. Kudo, T. and S. Sutou, Molecular cloning of chicken FTZ-F1-related orphan receptors. Gene, 1997. 197(1-2): p. 261-8.
4. Boerboom, D., N. Pilon, R. Behdjani, D.W. Silversides, and J. Sirois, Expression and regulation of transcripts encoding two members of the NR5A nuclear receptor subfamily of orphan nuclear receptors, steroidogenic factor-1 and NR5A2, in equine ovarian cells during the ovulatory process. Endocrinology, 2000. 141(12): p. 4647-56.
5. Broadus, J., J.R. McCabe, B. Endrizzi, C.S. Thummel, and C.T. Woodard, The Drosophila beta FTZ-F1 orphan nuclear receptor provides competence for stage-specific responses to the steroid hormone ecdysone. Mol Cell, 1999. 3(2): p. 143-9.
6. Ellinger-Ziegelbauer, H., A.K. Hihi, V. Laudet, H. Keller, W. Wahli, and C. Dreyer, FTZ-F1-related orphan receptors in Xenopus laevis: transcriptional regulators differentially expressed during early embryogenesis. Mol Cell Biol, 1994. 14(4): p. 2786-97.
7. Lavorgna, G., H. Ueda, J. Clos, and C. Wu, FTZ-F1, a steroid hormone receptor-like protein implicated in the activation of fushi tarazu. Science, 1991. 252(5007): p. 848-51.
8. Li, Y., M. Choi, G. Cavey, J. Daugherty, K. Suino, A. Kovach, N.C. Bingham, S.A. Kliewer, and H.E. Xu, Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol Cell, 2005. 17(4): p. 491-502.
9. Solomon, I.H., J.M. Hager, R. Safi, D.P. McDonnell, M.R. Redinbo, and E.A. Ortlund, Crystal structure of the human LRH-1 DBD-DNA complex reveals Ftz-F1 domain positioning is required for receptor activity. J Mol Biol, 2005. 354(5): p. 1091-102.
10. Krylova, I.N., E.P. Sablin, J. Moore, R.X. Xu, G.M. Waitt, J.A. MacKay, D. Juzumiene, J.M. Bynum, K. Madauss, V. Montana, L. Lebedeva, M. Suzawa, J.D. Williams, S.P. Williams, R.K. Guy, J.W. Thornton, R.J. Fletterick, T.M. Willson, and H.A. Ingraham, Structural Analyses Reveal Phosphatidyl Inositols as Ligands for the NR5 Orphan Receptors SF-1 and LRH-1. Cell, 2005. 120(3): p. 343-355.
11. Luo, X., Y. Ikeda, and K.L. Parker, A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell, 1994. 77(4): p. 481-90.
12.Chand, A., K.A. Herridge, E.W. Thompson, and C. Clyne, The orphan nuclear receptor LRH1 promotes breast cancer motility and invasion. Endocr Relat Cancer, 2010.
Summary, Summary AID, CBI, purchased, synthesized, counterscreen, nuclear receptor, library, liver receptor homolog 1; liver receptor homolog-1; nuclear receptor NR5A2; nuclear receptor subfamily 5 group A member 2, LRH1, liver, inhibitor, inverse agonist, transcriptional assay, assay provider, center based initiative, center-based, luciferase, luminescence, selective, Scripps Florida, The Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Summary of Probe Development Effort:
This probe development effort is focused on the identification of inverse agonists of the liver receptor homolog-1 (LRH1; NR5A2). All AIDs that contain results associated with this project can be found in the "Related Bioassays" section of this Summary AID.
Categorized Comment - additional comments and annotations
Assay Cell Type: MDA-MB-231
From MLP Probe Report:
Probe count: 2
MLP Probe ML# for probe 1: ML180
PubChem Substance ID (SID) for probe 1: 99344023
PubChem Compound ID (CID) for probe 1: 3238389
Probe type for probe 1: Inverse Agonist
IC50/EC50 (nM) for probe 1: 3700
Target for probe 1: LRH1 (NR5A2) (gi: 4504343)
Disease relevance for probe 1: Breast Cancer
Anti-target for probe 1: SF1 (NR5A1)
Fold selectivity for probe 1: 2.7
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK110132/ (ID: 2990484)
Grant number for probe 1: MH084512
MLP Probe ML# for probe 2: ML179
PubChem Substance ID (SID) for probe 2: 92092843
PubChem Compound ID (CID) for probe 2: 45100448
IC50/EC50 (nM) for probe 2: 320
Fold selectivity for probe 2: 31.25
NCBI Book chapter title for probe 1: Discovery of Inverse Agonists for the Liver Receptor Homologue-1 (LRH1; NR5A2)