title: Finerenone Impedes Aldosterone-dependent Nuclear Import of the Mineralocorticoid Receptor and Prevents Genomic Recruitment of Steroid Receptor Coactivator-1.
abstract: Aldosterone regulates sodium homeostasis by activating the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Hyperaldosteronism leads todeleterious effects on the kidney, blood vessels, and heart. Although steroidal antagonists such as spironolactone and eplerenone are clinically useful for the treatment of cardiovascular diseases, they are associated with several side effects. Finerenone, a novel nonsteroidal MR antagonist, is presently being evaluated in two clinical phase IIb trials. Here, we characterized the molecular mechanisms of action of finerenone and spironolactone at several key steps of the MR signaling pathway. Molecular modeling and mutagenesis approaches allowed identification of Ser-810 and Ala-773 as key residues for the high MR selectivity of finerenone. Moreover, we showed that, in contrast to spironolactone, which activates the S810L mutant MR responsible for a severe form of early onset hypertension, finerenone displays strict antagonistic properties. Aldosterone-dependent phosphorylation and degradation of MR are inhibited by both finerenone and spironolactone. However, automated quantification of MR subcellular distribution demonstrated that finerenone delays aldosterone-induced nuclear accumulation of MR more efficiently than spironolactone. Finally, chromatin immunoprecipitation assays revealed that, as opposed to spironolactone, finerenone inhibits MR, steroid receptor coactivator-1, and RNA polymerase II binding at the regulatory sequence of the SCNN1A gene and also remarkably reduces basal MR and steroid receptor coactivator-1 recruitment, unraveling a specific and unrecognized inactivating mechanism on MR signaling. Overall, our data demonstrate that the highly potent and selective MR antagonist finerenone specifically impairs several critical steps of the MR signaling pathway and therefore represents a promising new generation MR antagonist.
authors.affiliation: From the INSERM, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, the Faculté de Médecine Paris-Sud, Université Paris-Sud, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, UMS 32, Institut Biomédical de Bicêtre, Le Kremlin-Bicêtre F-94276, France.
authors.forename: Larbi
authors.initials: L
authors.lastname: Amazit
authors.affiliation: From the INSERM, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, the Faculté de Médecine Paris-Sud, Université Paris-Sud, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Le Billan
authors.affiliation: the Departments of Cardiology Research and.
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
authors.affiliation: From the INSERM, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, the Faculté de Médecine Paris-Sud, Université Paris-Sud, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France.
authors.forename: Khadija
authors.initials: K
authors.lastname: Lamribet
authors.affiliation: From the INSERM, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, the Faculté de Médecine Paris-Sud, Université Paris-Sud, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France.
authors.forename: Say
authors.initials: S
authors.lastname: Viengchareun
authors.affiliation: INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3, 75890 Paris, France, and the Université Paris-Denis Diderot, Site Bichat, Paris, France.
authors.forename: Michel R
authors.initials: MR
authors.lastname: Fay
authors.affiliation: From the INSERM, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, the Faculté de Médecine Paris-Sud, Université Paris-Sud, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France.
authors.forename: Junaid A
authors.initials: JA
authors.lastname: Khan
authors.affiliation: Medicinal Chemistry, Bayer Pharma AG, Global Drug Discovery, 42113 Wuppertal, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillisch
authors.affiliation: From the INSERM, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, the Faculté de Médecine Paris-Sud, Université Paris-Sud, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Lombès
authors.affiliation: INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3, 75890 Paris, France, and the Université Paris-Denis Diderot, Site Bichat, Paris, France.
authors.forename: Marie-Edith
authors.initials: ME
authors.lastname: Rafestin-Oblin
authors.affiliation: From the INSERM, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, the Faculté de Médecine Paris-Sud, Université Paris-Sud, UMR-S 1185, Le Kremlin-Bicêtre F-94276, France, INSERM U773, Centre de Recherche Biomédicale Bichat-Beaujon, CRB3, 75890 Paris, France, and the Université Paris-Denis Diderot, Site Bichat, Paris, France jerome.fagart@inserm.fr.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fagart
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000450:Aldosterone / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D053503:Epithelial Sodium Channels / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008856:Microscopy, Fluorescence; D009154:Mutation; D009287:Naphthyridines / Q000494:pharmacology*; D056920:Nuclear Receptor Coactivator 1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D053503:Epithelial Sodium Channels; D009287:Naphthyridines; D018161:Receptors, Mineralocorticoid; C507045:SCNN1A protein, human; C576501:finerenone; D013148:Spironolactone; D000450:Aldosterone; D056920:Nuclear Receptor Coactivator 1
keywords: aldosterone; antagonist; cardiovascular disease; drug action; heart; inhibition mechanism; inhibitor; mechanism of action; mineralocorticoid receptor; steroid hormone receptor