2. Academic Validation
  3. GNS561 (ezurpimtrostat), a small basic lipophilic molecule, prevents lupus phenotype in a pristane-induced lupus mouse model

GNS561 (ezurpimtrostat), a small basic lipophilic molecule, prevents lupus phenotype in a pristane-induced lupus mouse model

  • Br J Pharmacol. 2025 Aug;182(16):3786-3799. doi: 10.1111/bph.70058.
Eya Toumi 1 2,  Eloïne Bestion 3,  Muriel Militello 1,  Hubert Lepidi 1,  Anne Plauzolles 2,  Nathalie Bardin 4 5,  Daniel Bertin 5,  Laurent Chiche 6,  Jean-Louis Mege 5 7,  Philippe Halfon 1 2 3 8,  Soraya Mezouar 7 9
Affiliations

Affiliations

  • 1 Aix-Marseille Univ, Microbe, Evolution, Phylogenie et Infection, Assistance Publique- Hopitaux de Marseille, Marseille, France.
  • 2 Laboratoire Alphabio, Marseille, France.
  • 3 Genoscience Pharma, Marseille, France.
  • 4 Aix Marseille Univ, Institut National de la Santé et de la Recherche Médicale, Centre de recherche en CardioVasculaire et Nutrition, Marseille, France.
  • 5 Service d'Immunologie, Biogénopôle, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
  • 6 Unité de Médecine Interne et Recherche Clinique, Hôpital Européen Marseille, Marseille, France.
  • 7 Aix-Marseille Univ, Centre National de la Recherche Scientifique, Établissement Français du Sang, Anthropologie bio-culturelle, Droit, Éthique et Santé, Marseille, France.
  • 8 Infectious and Internal Medicine Department, Hôpital Européen Marseille, Marseille, France.
  • 9 Faculty of Medical and Paramedical Sciences, Aix-Marseille University, HIPE Human Lab, Marseille, France.
PMID: 40258389 DOI: 10.1111/bph.70058
Abstract

Background and purpose: Systemic lupus erythematosus is an autoimmune, multisystemic disease affecting all organs in the body. Accrued evidence has elucidated a role for Autophagy in the onset and severity of systemic lupus erythematosus. The antimalarial drug hydroxychloroquine constitutes the cornerstone of standard of care for systemic lupus erythematosus, together with glucocorticoids and immunosuppressants or biologics, and all accompanied by various side effects.

Experimental approach and objective: Our study aimed to investigate the potential of GNS561 (ezurpimtrostat) treatment, a small basic lipophilic molecule that induces lysosomal dysregulation, using the pristane-induced lupus mouse model.

Key results: Compared with hydroxychloroquine, GNS561 treatment presents a more pronounced impact on the development of pathogenic anti-antibodies in pristane-induced lupus mice. Next, focussing on clinical impact, we showed that GNS561 significantly reduced clinical signs of lupus in pristane-induced lupus by preventing the incidence and severity of arthritis, occurrence of nephritis and lung damage. Finally, GNS561 modulated the inflammatory profile in pristane-induced lupus mice through a reduction of the lipogranuloma score. Interestingly, focussing on interferon-α, only pristane-induced lupus mice treated by GNS561 presented a significant decrease of the cytokine, suggesting a higher efficacy for GNS561 in the modulation of lupus-induced inflammation compared with hydroxychloroquine.

Conclusion: All results show that GNS561, but not hydroxychloroquine, represents as an effective treatment to prevent clinical and inflammatory signs of lupus in this mouse model.

Implications: Altogether, this study highlights GNS561 as a promising investigational drug for systemic lupus erythematosus.

Keywords

GNS561/ezurpimtrostat; autophagy; hydroxychloroquine; pristane‐induced lupus (PIL) mice model; systemic lupus erythematosus.

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