Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy.

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Heier CR, Yu Q, Fiorillo AA, Tully CB, Tucker A, Mazala DA, Uaesoontrachoon K, Srinivassane S, Damsker JM, Hoffman EP, Nagaraju K, Spurney CF

Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy.

Life Sci Alliance. 2019 Feb 11;2(1):e201800186. doi: 10.26508/lsa.201800186. Print 2019 Feb.

PubMed ID

30745312 [ View in PubMed

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Abstract

Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle pathophysiology. Comparisons of their ligand structures indicate that the Delta9,11 modification of the first-in-class drug vamorolone enables it to avoid interaction with a conserved receptor residue (N770/N564), which would otherwise activate transcription factor properties of both receptors. Reporter assays show that vamorolone and eplerenone are MR antagonists, whereas prednisolone is an MR agonist. Macrophages, cardiomyocytes, and CRISPR knockout myoblasts show vamorolone is also a dissociative GR ligand that inhibits inflammation with improved safety over prednisone and GR-specific deflazacort. In mice, hyperaldosteronism activates MR-driven hypertension and kidney phenotypes. We find that genetic dystrophin loss provides a second hit for MR-mediated cardiomyopathy in Duchenne muscular dystrophy model mice, as aldosterone worsens fibrosis, mass and dysfunction phenotypes. Vamorolone successfully prevents MR-activated phenotypes, whereas prednisolone activates negative MR and GR effects. In conclusion, vamorolone targets dual nuclear receptors to treat inflammation and cardiomyopathy with improved safety.

DrugBank Data that Cites this Article

Drugs

Vamorolone

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Vamorolone	Mineralocorticoid receptor	Protein	Humans	Unknown	Antagonist	Details