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

Xiong, Yan; Li, Fengling; Babault, Nicolas; Wu, Hong; Dong, Aiping; Zeng, Hong; Chen, Xin; Arrowsmith, C.H.; Brown, Peter J.; Liu, Jing; Vedadi, Masoud; Jin, Jian

doi:10.1016/j.bmc.2017.06.021

Cited by 26 publications

(25 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The interaction of 5‐Aza‐dC, (a known inhibitor of DNMTs) and TSA (known inhibitor of HDACs) was also previously described by us and used as a reference to compare quercetin's interaction. Likewise, G9A (PDB ID: 5VSC) and EZH2 (PDB ID: 5LS6) structure were retrieved from RCSB and prepared for docking . Quercetin was docked to these protein structures using SwissDock server and the least energy model was used for further analysis using UCSF‐Chimaera …”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells

Sundaram¹,

Hussain²,

Haque

et al. 2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

The central role of epigenomic alterations in carcinogenesis has been widely acknowledged, particularly the impact of DNA methylation on gene expression across all stages of carcinogenesis is considered vital for both diagnostic and therapeutic strategies. Dietary phytochemicals hold great promise as safe anticancer agents and effective epigenetic modulators. This study was designed to investigate the potential of a phytochemical, quercetin as a modulator of the epigenetic pathways for anticancer strategies. Biochemical activity of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and global genomic DNA methylation was quantitated by an enzyme‐linked immunosorbent assay based assay in quercetin‐treated HeLa cells. Molecular docking studies were performed to predict the interaction of quercetin with DNMTs and HDACs. Quantitative methylation array was used to assess quercetin‐mediated alterations in the promoter methylation of selected tumor suppressor genes (TSGs). Quercetin induced modulation of chromatin modifiers including DNMTs, HDACs, histone acetyltransferases (HAT) and HMTs, and TSGs were assessed by quantitative reverse transcription PCR (qRT‐PCR). It was found that quercetin modulates the expression of various chromatin modifiers and decreases the activity of DNMTs, HDACs, and HMTs in a dose‐dependent manner. Molecular docking results suggest that quercetin could function as a competitive inhibitor by interacting with residues in the catalytic cavity of several DNMTs and HDACs. Quercetin downregulated global DNA methylation levels in a dose‐ and time‐dependent manner. The tested TSGs showed steep dose‐dependent decline in promoter methylation with the restoration of their expression. Our study provides an understanding of the quercetin's mechanism of action and will aid in its development as a candidate for epigenetic‐based anticancer therapy.

show abstract

Section: Methodsmentioning

confidence: 99%

“…Likewise, G9A (PDB ID: 5VSC) and EZH2 (PDB ID: 5LS6) structure were retrieved from RCSB and prepared for docking. 21,22 Quercetin was docked to these protein structures using SwissDock server 23 and the least energy model was used for further analysis using UCSF-Chimaera. 24 2.7 | Global DNA methylation quantitation assay…”

Section: Hmt-h3k9 Activity Assaymentioning

confidence: 99%

Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells

Sundaram¹,

Hussain²,

Haque

et al. 2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

show abstract

“…Substrate competitive inhibitors act by binding to G9a substrate binding sites, while SAM inhibitors prevent G9a-mediated methylation by interacting with SAM binding sites on G9a [ 52 ]. Most of these inhibitors also impact GLP [ 53 ].…”

Section: Biochemical Featuresmentioning

confidence: 99%

Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Poulard

Noureddine

Pruvost

et al. 2021

Life

View full text Add to dashboard Cite

G9a is a lysine methyltransferase catalyzing the majority of histone H3 mono- and dimethylation at Lys-9 (H3K9), responsible for transcriptional repression events in euchromatin. G9a has been shown to methylate various lysine residues of non-histone proteins and acts as a coactivator for several transcription factors. This review will provide an overview of the structural features of G9a and its paralog called G9a-like protein (GLP), explore the biochemical features of G9a, and describe its post-translational modifications and the specific inhibitors available to target its catalytic activity. Aside from its role on histone substrates, the review will highlight some non-histone targets of G9a, in order gain insight into their role in specific cellular mechanisms. Indeed, G9a was largely described to be involved in embryonic development, hypoxia, and DNA repair. Finally, the involvement of G9a in cancer biology will be presented.

show abstract

“…Catalytic domains of Human G9a (913–1193) and GLP (982–1266) were cloned, expressed, and purified as previously described [ 34 ]. Full length of S. solfataricus S-adenosylhomocysteine hydrolase (SAHH) was cloned, expressed, and purified using the published protocol [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors

Luise

Robaa

Regenass

et al. 2021

IJMS

Self Cite

View full text Add to dashboard Cite

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.

show abstract

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

Cited by 26 publications

References 52 publications

Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells

Quercetin modifies 5′CpG promoter methylation and reactivates various tumor suppressor genes by modulating epigenetic marks in human cervical cancer cells

Structure, Activity, and Function of the Protein Lysine Methyltransferase G9a

Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors

Contact Info

Product

Resources

About