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

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.

Figure 1

Schematic representation of epigenetics and its key mechanisms linking the genome to environmental influences. The diagram illustrates three main epigenetic processes: DNA methylation, histone modifications, and noncoding RNA regulation. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 2

Comprehensive overview of findings in Alzheimer's disease (AD) following pharmacological inhibition or genetic modification of G9a. This schematic diagram illustrates the multifaceted effects of G9a modulation on various pathological aspects of AD. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3

Comprehensive overview of findings in Parkinson's disease (PD) following pharmacological inhibition or genetic modification of G9a. This schematic diagram illustrates the multifaceted effects of G9a modulation on various aspects of PD pathology. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 4

Comprehensive overview of findings in Huntington's disease (HD) following pharmacological inhibition or genetic modification of G9a. This schematic diagram illustrates the multifaceted effects of G9a modulation on various aspects of HD pathology. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 5

Comprehensive overview of findings in autism spectrum disorder (ASD) following pharmacological inhibition or genetic modification of G9a. This schematic diagram illustrates the multifaceted effects of G9a modulation on various aspects of ASD pathology. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 6

Comprehensive overview of findings in neuropsychiatric disorders following pharmacological inhibition or genetic modification of G9a. This schematic diagram illustrates the multifaceted effects of G9a modulation on various aspects of schizophrenia (SZ) and major depressive disorder (MDD) pathology. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 7

Rational design and synthesis of G9a inhibitors (Part I): Schematic illustration of the structure–activity relationship (SAR) studies and key modifications leading to the development of potent G9a inhibitors. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 8

Rational design and synthesis of G9a inhibitors (Part II): Schematic illustration of further structure–activity relationship (SAR) studies and key modifications leading to the development of more potent and selective G9a inhibitors. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 9

Rational design and synthesis of G9a inhibitors (Part III): Schematic illustration of further structure–activity relationship (SAR) studies and key modifications leading to the development of more potent and selective G9a inhibitors. [Color figure can be viewed at wileyonlinelibrary.com]

Figure 10

New G9a inhibitors discovered via computational methods.