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ChemDiv’s library of small molecule compounds targeting G9a comprises 11,009 entries.

G9a is a histone methyltransferase that plays a critical role in the epigenetic regulation of gene expression through its enzymatic activity, specifically in the methylation of histone H3 on lysine 9 (H3K9). This modification leads to a repressive chromatin state, thereby influencing cell differentiation, proliferation, and survival processes. Aberrant G9a activity has been implicated in the development of various diseases, including cancer, where its overexpression or deregulation contributes to tumorigenesis by silencing tumor suppressor genes and modifying the tumor microenvironment. Additionally, G9a's involvement extends to neurological disorders, where its dysregulation affects neuronal development and function, potentially contributing to the pathophysiology of diseases such as depression and neurodegeneration. Through these mechanisms, G9a serves as a key molecular player in the intricate balance of gene expression regulation, with its dysfunction leading to the emergence and progression of diverse pathological conditions.

G9a is considered a promising target for drug discovery due to its pivotal role in epigenetic modifications and its broad involvement in various diseases, particularly cancer and neurological disorders. As an enzyme responsible for histone methylation, G9a plays a crucial role in the epigenetic regulation of gene expression. Targeting G9a offers a way to modulate gene expression patterns implicated in disease states, potentially reversing abnormal gene silencing or activation. The enzymatic activity of G9a provides a clear target for small molecule inhibitors, some of which have already shown promise in preclinical studies. These inhibitors can selectively block G9a's methyltransferase activity, leading to reactivation of silenced genes and the suppression of disease phenotypes. The ability to design inhibitors that specifically target G9a's enzymatic function reduces the risk of off-target effects, a common challenge in drug development. This specificity could lead to more effective and safer therapeutic options for patients.

ChemDiv's compound library targeting G9a for drug discovery encompasses a sophisticated selection of molecules centered around a single scaffold known for its high potency as G9a inhibitors. This core structure has been extensively analyzed, with comprehensive structure-activity relationship (SAR) data available, highlighting its effectiveness and potential for therapeutic application. This foundational research, detailed in the work of Feng Liu and colleagues [1], has led to the characterization and in vitro evaluation of 29 distinct compounds, alongside the acquisition of crystallographic data for several key molecules, underscoring the depth of understanding and potential for further optimization.

In advancing this promising start, ChemDiv's strategy focuses on generating close isosteric analogs that maintain the scaffold's effective topology while preserving essential binding points identified through rigorous analysis. This approach leverages a 2D-similarity strategy aimed at active compounds, incorporating a "targeted diversity" set that includes, for example, tyrosine kinase inhibitors, to broaden the therapeutic impact and applicability of the library.

To refine and enhance the library's potential, ChemDiv employs advanced computational techniques, including 3D-molecular docking and pharmacophore modeling/searching. These methods enable a deeper exploration of the compounds' interactions with G9a, facilitating the identification of molecules with optimized efficacy and specificity. Through this multifaceted approach, ChemDiv is at the forefront of developing a targeted and diverse library of compounds with the potential to revolutionize G9a-targeted drug discovery.


[1] Feng Liu et al. Protein Lysine Methyltransferase G9a Inhibitors: Design, Synthesis, and Structure Activity Relationships of 2,4-Diamino-7-aminoalkoxy- quinazolines. J Med Chem. 2010, 53, 5844–5857

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