Synthesis and in Vitro Evaluation of Biotinylated RG108:  A High Affinity Compound for Studying Binding Interactions with Human DNA Methyltransferases

Schirrmacher, Esther; Beck, Carmen; Brueckner, Bodo; Schmitges, Frank W.; Siedlecki, Paweł; Bartenstein, Peter; Lyko, Frank; Schirrmacher, Ralf

doi:10.1021/bc050300b

Cited by 41 publications

(33 citation statements)

References 19 publications

(31 reference statements)

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“…The DNMT1 inhibitor RG108 prevents DNA methylation by blocking the DNA-binding pocket of DNMT (Schirrmacher et al 2006). In this study, we investigated the effect of DNMT inhibition in ALS-MSCs and observed the prevention of cellular senescence and recovery of neural differentiation capacity.…”

Section: Introductionmentioning

confidence: 99%

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase

Kim

Cho

2015

Cell Mol Neurobiol

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Alteration of DNA methylation is highly associated with aging and neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Remedying these aberrant methylation patterns may serve to improve these diseases. Previously, we reported that human bone marrow mesenchymal stromal cells isolated from ALS patients (ALS-MSCs) have functionally decreased stem cell potency, and excessively express DNA methyltransferases (DNMTs). In this study, we examined the correlation between excessive DNMT expression and functional decline in ALS-MSCs. The DNMT inhibitor RG108 was used for this. RG108-treated ALS-MSCs exhibit increased expression of the anti-senescence genes TERT, VEGF, and ANG, and decreased expression of the senescence-related genes ATM and p21. The activity of SA-β-galactosidase and the expression of senescence proteins p53 and p16 were reduced in RG108-treated ALS-MSCs. The abilities of cell migration and protection against oxidative damage were improved in the treated ALS-MSCs. In neuronal differentiation experiments, the treated MSCs more effectively differentiated into neuron-like cells. These results suggest that ALS-MSC function can be restored by inhibiting excessively expressed DNMTs, an approach that may ultimately provide better efficacy in stem cell therapy.

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Section: Introductionmentioning

confidence: 99%

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase

Kim

Cho

2015

Cell Mol Neurobiol

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“…This group includes curcumin [31][32][33], parthenolide [34][35][36][37][38], and RG108-1 [39], a maleimide analogue of RG108 (vide infra); (3) non-nucleoside and non-covalent blockers such as hydralazine [40][41][42][43][44], procaine [45][46][47], procainamide [41,48], (-)-epigallocatechin-3-gallate (EGCG) [49][50][51][52][53], and mahanine [54,55]; and (4) non-covalent blockers identified from virtual screening such as RG108 [56][57][58] and NSC14778 [59,60]. Some of these compounds are drugs approved for other indications such as hydralazine, procaine, and procainamide (vide infra).…”

Section: Introductionmentioning

confidence: 99%

Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase

Yoo

Medina‐Franco

2011

J Comput Aided Mol Des

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DNA methyltransferase 1 (DNMT1) is an emerging epigenetic target for the treatment of cancer and other diseases. To date, several inhibitors from different structural classes have been published. In this work, we report a comprehensive molecular modeling study of 14 established DNTM1 inhibitors with a herein developed homology model of the catalytic domain of human DNTM1. The geometry of the homology model was in agreement with the proposed mechanism of DNA methylation. Docking results revealed that all inhibitors studied in this work have hydrogen bond interactions with a glutamic acid and arginine residues that play a central role in the mechanism of cytosine DNA methylation. The binding models of compounds such as curcumin and parthenolide suggest that these natural products are covalent blockers of the catalytic site. A pharmacophore model was also developed for all DNMT1 inhibitors considered in this work using the most favorable binding conformations and energetic terms of the docked poses. To the best of our knowledge, this is the first pharmacophore model proposed for compounds with inhibitory activity of DNMT1. The results presented in this work represent a conceptual advance for understanding the protein-ligand interactions and mechanism of action of DNMT1 inhibitors. The insights obtained in this work can be used for the structure-based design and virtual screening for novel inhibitors targeting DNMT1.

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“…Both drugs were approved by the Food and Drug Administration for the treatment of myelodysplastic syndrome in 2004 and 2006, respectively, and represent the first DNMT inhibitors in clinical use. One of the most recent approaches is the rational development of small-molecule nonnucleoside inhibitors such as RG108 (11)(12)(13). The family of nonnucleoside candidate DNMT inhibitors is steadily growing and comprises a large variety of different chemical scaffolds [e.g., polyphenolic compounds such as epigallocatechin-3-gallate (14,15) or compounds with acidic functions such as caffeic acid (16) or methylenedisalicylic acid (17)].…”

Section: Introductionmentioning

confidence: 99%

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

Kuck

Caulfield

Lyko

et al. 2010

Molecular Cancer Therapeutics

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115

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Enzymes involved in the epigenetic regulation of the genome represent promising starting points for therapeutic intervention by small molecules, and DNA methyltransferases (DNMT) are emerging targets for the development of a new class of cancer therapeutics. In this work, we present nanaomycin A, initially identified by a virtual screening for inhibitors against DNMT1, as a compound inducing antiproliferative effects in three different tumor cell lines originating from different tissues. Nanaomycin A treatment reduced the global methylation levels in all three cell lines and reactivated transcription of the RASSF1A tumor suppressor gene. In biochemical assays, nanaomycin A revealed selectivity toward DNMT3B. To the best of our knowledge, this is the first DNMT3B-selective inhibitor identified to induce genomic demethylation. Our study thus establishes the possibility of selectively inhibiting individual DNMT enzymes. Mol Cancer Ther; 9(11); 3015-23.

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Synthesis and in Vitro Evaluation of Biotinylated RG108: A High Affinity Compound for Studying Binding Interactions with Human DNA Methyltransferases

Cited by 41 publications

References 19 publications

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase

Functional Restoration of Amyotrophic Lateral Sclerosis Patient-Derived Mesenchymal Stromal Cells Through Inhibition of DNA Methyltransferase

Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase

Nanaomycin A Selectively Inhibits DNMT3B and Reactivates Silenced Tumor Suppressor Genes in Human Cancer Cells

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