| Autor: |
Schoepke E; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States.; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, Missouri 63110, United States., Billon C; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, Missouri 63110, United States., Haynes KM; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States., Avdagic A; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States., Sitaula S; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States., Sanders R; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, Missouri 63110, United States., Adeyemi CM; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States., Walker JK; Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104, United States.; Department of Chemistry, Saint Louis University, St. Louis, Missouri 63103, United States., Burris TP; Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, Missouri 63110, United States.; Department of Chemistry, Saint Louis University, St. Louis, Missouri 63103, United States. |
| Abstrakt: |
The estrogen related receptors (ERRs) are a subgroup of nuclear receptors that play a role in regulation of cellular metabolism. Prostate cancer (PCa) cells display altered metabolic signatures, such as the Warburg effect, and the ERRs have been implicated in driving this phenotype. Despite the lack of a known endogenous ligand, synthetic ligands that target the ERRs have been discovered. For example, the ERRα inverse agonist XCT790 modulates metabolic pathways in PCa cells, but it also functions as a mitochondrial uncoupler independent of targeting ERRα. Here, we describe a novel dual ERRα/γ inverse agonist, SLU-PP-1072, derived from the GSK4716 ERRγ agonist scaffold that is distinct from the XCT790 scaffold. SLU-PP-1072 alters PCa cell metabolism and gene expression, resulting in cell cycle dysregulation and increased apoptosis without acute mitochondrial uncoupling activity. Our data suggest that inhibition of ERRα/γ may be beneficial in treatment of PCa, and SLU-PP-1072 provides a unique chemical tool to evaluate the pharmacology of ERRα and ERRγ. |
