Targeting H3K9 methyltransferase G9a and its related molecule GLP as a potential therapeutic strategy for cancer

Abstract

H3K9 methyltransferase (G9a) and its relevant molecule GLP are the SET domain proteins that specifically add mono, di and trimethyl groups on to the histone H3K9, which lead to the transcriptional inactivation of chromatin and reduce the expression of cancer suppressor genes, which trigger growth and progress of several cancer types. Various studies have demonstrated that overexpression of H3K9 methyltransferase G9a and GLP in different kinds of tumors, like lung, breast, bladder, colon, cervical, gastric, skin cancers, hepatocellular carcinoma and hematological malignancies. Several G9a and GLP inhibitors such as BIX‐01294, UNC0642, A‐366 and DCG066 were developed to combat various cancers; however, there is a need for more effective and less toxic compounds. The current molecular docking study suggested that the selected new compounds such as ninhydrin, naphthoquinone, cysteamine and disulfide cysteamine could be suitable molecules as a G9a and GLP inhibitors. Furthermore, detailed cell based and preclinical animal studies are required to confirm their properties. In the current review, we discussed the role of G9a and GLP mediated epigenetic regulation in the cancers. A thorough literature review was done related to G9a and GLP. The databases used extensively for retrieval of information were PubMed, Medline, Scopus and Science‐direct. Further, molecular docking was performed using Maestro Schrodinger version 9.2 software to investigate the binding profile of compounds with Human G9a HMT (PDB ID: 3FPD, 3RJW) and Human GLP MT (PDB ID: 6MBO, 6MBP).

Lysine methyltransferase inhibitors: where we are now

“…22 reduces dimethylated H3K9 levels in different G9a target genes, promoting autophagy-dependent cell death and reducing cell proliferation in different types of cancer cell lines, such as colorectal, breast, bladder cancer and glioma cells. [74][75][76] Insertion of the 5-aminopentyloxy on 22 to mimic the lysine side chain, yielded 23 (E72), which retains similar activity to 22 but displays very low cytotoxicity. 77 The 2,4-diamino-6,7dimethoxyquinazoline core was identified as key pharmacophore and structure-activity relationship (SAR) investigation allowed the identification of several derivatives.…”

EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

“…UNC0638 and other inhibitors are examples of a class of substrate competitive inhibitors, which directly occupy the binding site of the histone to G9a and specifically bind the substrate site in G9a, whereas other compounds constitute a second class of agents that act as competitive inhibitors of the S-adenosyl-methionine (SAM) cofactor [89]. Molecular docking experiments have identified compounds, including ninhydrin, naphthoquinone, cysteamine, and disulfide cysteamine as candidate G9a and GLP inhibitors [92]. In spite of these considerable advances in drug discovery, to date G9a inhibitors have not been evaluated in clinical trials [93,94].…”

EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

“…UNC0638 and other inhibitors are examples of a class of substrate competitive inhibitors, which directly occupy the binding site of the histone to G9a and specifically bind the substrate site in G9a, whereas other compounds constitute a second class of agents that act as competitive inhibitors of the Sadenosyl-methionine (SAM) cofactor [43]. Molecular docking experiments have identified compounds including ninhydrin, naphthoquinone, cysteamine and disulfide cysteamine as candidate G9a and GLP inhibitors [46]. Further research should focus on identifying the possible differential sensitivities of distinct tumor molecular subgroups and subtypes to G9a inhibition, as well as in evaluating combinations of G9a inhibitors with other epigenetic or non-epigenetic anticancer agents, which may be a more promising approach compared to single-agent therapeutic strategies.…”