Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors

Srimongkolpithak, Nitipol; Sundriyal, Sandeep; Li, Fengling; Vedadi, Masoud; Fuchter, Matthew J.

doi:10.1039/c4md00274a

Cited by 37 publications

(40 citation statements)

References 44 publications

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“…We attempted to replace the N2 nitrogen atom of the quinazoline core with a carbon atom, which leads to a structurally distinct quinoline core. Although quinoline analogs were reported as equipotent GLP and G9a dual inhibitors, 42 GLP selective inhibitors with a quinoline core have not been reported. Thus, we prepared the quinoline analogs of MS0124 and MS012 for direct comparison.…”

Section: Resultsmentioning

confidence: 99%

“…1,2,30–42 High throughput screening led to the discovery of BIX01294 ( 1 ), which is the first potent and selective dual inhibitor of GLP and G9a. 1 Our group and others utilized structure-based design strategy in combination with SAR exploration and developed more potent compounds, such as UNC0224 ( 2 ), 37 UNC0321 ( 3 ), 38 and E72 ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

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Structure-activity relationship studies of G9a-like protein (GLP) inhibitors

Xiong

Babault

et al. 2017

Bioorganic & Medicinal Chemistry

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Given the high homology between the protein lysine methyltransferases G9a-like protein (GLP) and G9a, it has been challenging to develop potent and selective inhibitors for either enzyme. Recently, we reported two quinazoline compounds, MS0124 and MS012, as GLP selective inhibitors. To further investigate the structure–activity relationships (SAR) of the quinazoline scaffold, we designed and synthesized a range of analogs bearing different 2-amino substitutions and evaluated their inhibition potencies against both GLP and G9a. These studies led to the identification of two new GLP selective inhibitors, 13 (MS3748) and 17 (MS3745), with 59- and 65-fold higher potency for GLP over G9a, which were confirmed by isothermal titration calorimetry (ITC). Crystal structures of GLP and G9a in complex with 13 and 17 provide insight into the interactions of the inhibitors with both proteins. In addition, we generated GLP selective inhibitors bearing a quinoline core instead of the quinazoline core.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structure-activity relationship studies of G9a-like protein (GLP) inhibitors

Xiong

Babault

et al. 2017

Bioorganic & Medicinal Chemistry

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“…Examples of this include the broad-spectrum methyltransferase inhibitor BIX01338 25 and the more specific BIX01294 26, which has high potency against G9a and GLP [141,142]. The selectivity of 26 was tested against a panel of methyltransferases including sixteen KMTs, six PRMTs and one DNA methyltransferase, all of which tested negative with the exception of the KMTs SETD2 and EZH2, which showed moderate inhibition [143]. 26 appears to induce autophagy and death in MCF-7 cells by selective inhibition of Ga9 resulting in reduced H3K9 Inhibitors of histone lysine modifying enzymes Review methylation [144].…”

Section: Lysine Methyltransferase Inhibitorsmentioning

confidence: 99%

Inhibitors of Enzymes Catalyzing Modifications to Histone Lysine Residues: Structure, Function and Activity

et al. 2016

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Gene expression is partly controlled by epigenetic mechanisms including histone-modifying enzymes. Some diseases are caused by changes in gene expression that can be mitigated by inhibiting histone-modifying enzymes. This review covers the enzyme inhibitors targeting histone lysine modifications. We summarize the enzymatic mechanisms of histone lysine acetylation, deacetylation, methylation and demethylation and discuss the biochemical roles of these modifications in gene expression and in disease. We discuss inhibitors of lysine acetylation, deacetylation, methylation and demethylation defining their structure-activity relationships and their potential mechanisms. We show that there are potentially indiscriminant off-target effects on gene expression even with the use of selective epigenetic enzyme inhibitors.

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“…We have previously reported the EHMT2 IC50 of HKMTI-1-005, HKMTI-1-011 and HKMTI-1-022 to be 0.10, 3.19 and 0.47 μM, respectively [40]. This data was generated using a scintillation proximity assay (SPA) which monitors the transfer of a tritium-labelled methyl group from [ 3 H]S-adenosyl-L-methionine (SAM) to a biotinylated-H3 (1-25) peptide substrate, mediated by EHMT2.…”

Section: Hit Compounds Directly Inhibit Ezh2 and Ehmt1/2 And Are Subsmentioning

confidence: 99%

554 Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells

Brown¹,

Fuchter²,

Curry³

et al. 2014

European Journal of Cancer

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Background: Many cancers show aberrant silencing of gene expression and overexpression of histone methyltransferases. The histone methyltransferases (HKMT) EZH2 and EHMT2 maintain the repressive chromatin histone methylation marks H3K27me and H3K9me, respectively, which are associated with transcriptional silencing. Although selective HKMT inhibitors reduce levels of individual repressive marks, removal of H3K27me3 by specific EZH2 inhibitors, for instance, may not be sufficient for inducing the expression of genes with multiple repressive marks.

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Identification of 2,4-diamino-6,7-dimethoxyquinoline derivatives as G9a inhibitors

Abstract: With the aim of discovering novel G9a inhibitory chemotypes, we have identified a new quinoline inhibitor scaffold and better defined the pharmacophoric features of the central heterocycle.

Cited by 37 publications

References 44 publications

Structure-activity relationship studies of G9a-like protein (GLP) inhibitors

Structure-activity relationship studies of G9a-like protein (GLP) inhibitors

Inhibitors of Enzymes Catalyzing Modifications to Histone Lysine Residues: Structure, Function and Activity

554 Dual EZH2 and EHMT2 histone methyltransferase inhibition increases biological efficacy in breast cancer cells

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