G9a an Epigenetic Therapeutic Strategy for Neurodegenerative Conditions: From Target Discovery to Clinical Trials

Aina Bellver-Sanchis; Marta Ribalta-Vilella; Alba Irisarri; Pinky Gehlot; Bhanwar Singh Choudhary; Abhisek Jana; Vivek Kumar Vyas; Deb Ranjan Banerjee; Mercè Pallàs; Ana Guerrero; Christian Griñán-Ferré

doi:10.1002/med.22096

G9a an Epigenetic Therapeutic Strategy for Neurodegenerative Conditions: From Target Discovery to Clinical Trials

Med Res Rev. 2025 Jan 6. doi: 10.1002/med.22096. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology and Therapeutic Chemistry, Institut de Neurociències-Universitat de Barcelona, Barcelona, Spain.
² Department of Pharmaceutical Chemistry, Institute of Pharmacy, Nirma University, Ahmedabad, India.
³ Department of Pharmacy, Central University of Rajasthan, Ajmer, India.
⁴ Drug Discovery and Development Centre (H3D), University of Cape Town, Rondebosch, South Africa.
⁵ Department of Chemistry, National Institute of Technology Durgapur, Durgapur, India.
⁶ Instituto de Salud Carlos III, Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.

PMID: 39763018
DOI: 10.1002/med.22096

Abstract

This review provides a comprehensive overview of the role of G9a/EHMT2, focusing on its structure and exploring the impact of its pharmacological and/or gene inhibition in various neurological diseases. In addition, we delve into the advancements in the design and synthesis of G9a/EHMT2 inhibitors, which hold promise not only as a treatment for neurodegeneration diseases but also for other conditions, such as cancer and malaria. Besides, we presented the discovery of dual therapeutic approaches based on G9a inhibition and different epigenetic enzymes like histone deacetylases, DNA methyltransferases, and other lysine methyltransferases. Hence, findings offer valuable insights into developing novel and promising therapeutic strategies targeting G9a/EHMT2 for managing these neurological conditions.

Keywords: EHMT2; G9a; aging; clinical trials; epigenetics; neurodegenerative conditions; small‐molecules.

Publication types

Review

Grants and funding

This study was supported by the Ministerio de Economía, Industria y Competitividad (Agencia Estatal de Investigación, AEI; to Christian Griñán-Ferré and Mercè Pallàs) and Fondo Europeo de Desarrollo Regional (MINECO-FEDER) (PID2022-139016OA-I00, PDC2022-133441-I00, PID2022-138829OA-I00; to Christian Griñán-Ferré, Mercè Pallàs and Ana Guerrero), Generalitat de Catalunya (2021 SGR 00357; to Christian Griñán-Ferré and Mercè Pallàs). This study was co-financed by Secretaria d'Universitats i Recerca del Departament d'Empresai Coneixement de la Generalitat de Catalunya 2022 (Producte 0092; Llavor 005 and 007; to Christian Griñán-Ferré). Ana Guerrero is the recipient of an Alzheimer's Association Research Fellowship (AARF-21-848511). Aina Bellver-Sanchis acknowledges the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) for her FI-SDUR fellowship (2021FISDU 00182).