Summary of probe development efforts to identify agonists of the steroid receptor coactivator 3 (SRC-3) recruitment by the peroxisome proliferator-activated receptor gamma (PPAR gamma)
Name: Summary of probe development efforts to identify agonists of the steroid receptor coactivator 3 (SRC-3) recruitment by the peroxisome proliferator-activated receptor gamma (PPAR gamma) ..more
Source (MLPCN Center Name): The Scripps Research Institute Molecular Screening Center (SRIMSC)
Center Affiliation: The Scripps Research Institute (TSRI)
Assay Provider: Pat Griffin, TSRI
Network: Molecular Library Probe Production Center Network (MLPCN)
Grant Proposal Number: 1 X01 MH079861-01
Grant Proposal PI: Patrick Griffin, TSRI
External Assay ID: PPARGSRC3_AG_LEADS_SUMMARY
Name: Summary of probe development efforts to identify agonists of the steroid receptor coactivator 3 (SRC-3) recruitment by the peroxisome proliferator-activated receptor gamma (PPAR gamma)
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and are lipid sensors functioning as ligand-dependent transcription factors regulating gene expression patterns of diverse biological processes (1, 2). PPARs play a critical role in metabolic processes such as glucose metabolism, lipid metabolism, and have been implicated in anti-atherogenic, anti-inflammatory as well as anti-hypertensive functions (3). Like other nuclear receptors, PPARs act as agonist-activated transcription factors, regulating specific target gene transcription. PPARs have been shown to respond to small molecules and are well-documented for therapeutic actions triggered by synthetic agonists (4-6). Among the three isoforms of PPAR identified, PPAR gamma (NR1C3) is implicated in several important disorders such as atherosclerosis, diabetes, obesity and cancer, providing strong justification for the search for specific PPARg agonists that can be used to treat these pathologies. However, the clinical use of PPARg agonists has been associated with adverse effects that are mainly caused by the concomitant activation of various target genes implicated in different physiological pathways. These side effects include weight gain through increased adipogenesis, renal fluid retention and plasma volume expansion, as well as toxic effects in the liver (7). To design safer and more selective PPARg agonists, the different physiological pathways triggered by PPARg activation have to be decoupled. Therefore, screening for agonists that favor specifically the association of a given cofactor will provide useful chemical tools for probing PPARg/coactivator interactions, helping the design of safer PPARg agonists.
Summary of Probe Development Effort:
Following primary HTS in singlicate to identify SRC3 agonists (AID 731), counterscreening in triplicate to identify possible fluorescent artifacts (AID 1048), confirmation of hit activity in triplicate (AID 1301), followed by titration assays in triplicate to determine potency of selective (AID 1331) and non-selective compounds (AID 1684), certain compounds were identified as possible candidates for probe development. A probe development effort is currently underway at the SRIMSC.
1. Chawla, A., et al., Nuclear receptors and lipid physiology: Opening the X-files. Science, 2001. 294(5548): p. 1866-1870.
2. Krey, G., et al., Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Molecular Endocrinology, 1997. 11(6): p. 779-791.
3. Bishop-Bailey, D., T. Hla, and T.D. Warner, Intimal smooth muscle cells as a target for peroxisome proliferator-activated receptor-gamma ligand therapy. Circ Res, 2002. 91(3): p. 210-7.
4. Evans, R.M., G.D. Barish, and Y.X. Wang, PPARs and the complex journey to obesity. Nat Med, 2004. 10(4): p. 355-61. PMID: 15057233.
5. Staels, B., et al., Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation, 1998. 98(19): p. 2088-93.
6. Barish, G.D., V.A. Narkar, and R.M. Evans, PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest, 2006. 116(3): p. 590-7.
7. Berger, J.P., T.E. Akiyama, and P.T. Meinke, PPARs: therapeutic targets for metabolic disease. Trends Pharmacol Sci, 2005. 26(5): p. 244-51.
Summary AID, PPAR gamma, PPARg, PPARG1, PPARG2, NR1C3, SRC-3, SRC3, nuclear receptor coactivator 3, NCOA3, RAC3, AIB1, ACTR, p/CIP, TRAM-1, CAGH16, TNRC16, agonist, agonism, activator, selective, non-selective, time-resolved fluorescence energy transfer, TR-FRET, FRET, 1536-well, HTS, High Throughput Screening, dose response, Scripps, Scripps Florida, Scripps Research Institute Molecular Screening Center, SRIMSC, Molecular Libraries Probe Production Centers Network, MLPCN.
Please see AIDs 731, 1048, 1301, 1331, and 1684 for all protocols performed in this probe development effort.