Selective disruption of NRF2-KEAP1 interaction leads to NASH resolution and reduction of liver fibrosis in mice.

Autor:	Seedorf K; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Weber C; Servier Research Institute of Medicinal Chemistry, Záhony u. 7., H-1031 Budapest, Hungary., Vinson C; Technologie Servier, 27 Rue Eugène Vignat, 45000 Orleans, France., Berger S; Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France., Vuillard LM; Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France., Kiss A; Servier Research Institute of Medicinal Chemistry, Záhony u. 7., H-1031 Budapest, Hungary., Creusot S; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Broux O; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Geant A; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Ilic C; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Lemaitre K; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Richard J; Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France., Hammoutene A; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France.; Université Paris Cité, Inserm, Centre de Recherche sur l'inflammation, F-75018 Paris, France., Mahieux J; Technologie Servier, 27 Rue Eugène Vignat, 45000 Orleans, France., Martiny V; Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France., Durand D; Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France., Melchiore F; Institut de Recherche Servier, 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France., Nyerges M; Servier Research Institute of Medicinal Chemistry, Záhony u. 7., H-1031 Budapest, Hungary., Paradis V; Département de Pathologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France., Provost N; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Duvivier V; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France., Delerive P; Cardiovascular and Metabolic Diseases Research, Institut de Recherches Servier, Suresnes, France.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2022 Dec 16; Vol. 5 (4), pp. 100651. Date of Electronic Publication: 2022 Dec 16 (Print Publication: 2023).
DOI:	10.1016/j.jhepr.2022.100651
Abstrakt:	Background & Aims: Oxidative stress is recognized as a major driver of non-alcoholic steatohepatitis (NASH) progression. The transcription factor NRF2 and its negative regulator KEAP1 are master regulators of redox, metabolic and protein homeostasis, as well as detoxification, and thus appear to be attractive targets for the treatment of NASH. Methods: Molecular modeling and X-ray crystallography were used to design S217879 - a small molecule that could disrupt the KEAP1-NRF2 interaction. S217879 was highly characterized using various molecular and cellular assays. It was then evaluated in two different NASH-relevant preclinical models, namely the methionine and choline-deficient diet (MCDD) and diet-induced obesity NASH (DIO NASH) models. Results: Molecular and cell-based assays confirmed that S217879 is a highly potent and selective NRF2 activator with marked anti-inflammatory properties, as shown in primary human peripheral blood mononuclear cells. In MCDD mice, S217879 treatment for 2 weeks led to a dose-dependent reduction in NAFLD activity score while significantly increasing liver Nqo1 mRNA levels, a specific NRF2 target engagement biomarker. In DIO NASH mice, S217879 treatment resulted in a significant improvement of established liver injury, with a clear reduction in both NAS and liver fibrosis. αSMA and Col1A1 staining, as well as quantification of liver hydroxyproline levels, confirmed the reduction in liver fibrosis in response to S217879. RNA-sequencing analyses revealed major alterations in the liver transcriptome in response to S217879, with activation of NRF2-dependent gene transcription and marked inhibition of key signaling pathways that drive disease progression. Conclusions: These results highlight the potential of selective disruption of the NRF2-KEAP1 interaction for the treatment of NASH and liver fibrosis. Impact and Implications: We report the discovery of S217879 - a potent and selective NRF2 activator with good pharmacokinetic properties. By disrupting the KEAP1-NRF2 interaction, S217879 triggers the upregulation of the antioxidant response and the coordinated regulation of a wide spectrum of genes involved in NASH disease progression, leading ultimately to the reduction of both NASH and liver fibrosis progression in mice. Competing Interests: All the authors are/were employees of Servier. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2022 The Author(s).)
Databáze:	MEDLINE
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